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Review

Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia

by
Seiichiro Katagiri
1,
SungGi Chi
2,
Yosuke Minami
2,*,
Kentaro Fukushima
3,
Hirohiko Shibayama
3,
Naoko Hosono
4,
Takahiro Yamauchi
4,
Takanobu Morishita
5,
Takeshi Kondo
6,
Masamitsu Yanada
7,
Kazuhito Yamamoto
7,
Junya Kuroda
8,
Kensuke Usuki
9,
Daigo Akahane
1 and
Akihiko Gotoh
1
1
Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
2
Department of Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277-8577, Japan
3
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
4
Department of Hematology and Oncology, University of Fukui Hospital, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
5
Division of Hematology, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya-shi, Aichi 453-8511, Japan
6
Blood Disorders Center, Aiiku Hospital, 2-1 S4 W25 Chuo-ku, Sapporo, Hokkaido 064-0804, Japan
7
Department of Hematology and Cell Therapy, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan
8
Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
9
Department of Hematology, NTT Medical Center Tokyo, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(9), 4694; https://doi.org/10.3390/ijms23094694
Submission received: 15 March 2022 / Revised: 20 April 2022 / Accepted: 22 April 2022 / Published: 23 April 2022
(This article belongs to the Special Issue Molecular Markers and Targets in Acute Myeloid Leukemia)
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Versions Notes

Abstract

:
KIT is a type-III receptor tyrosine kinase that contributes to cell signaling in various cells. Since KIT is activated by overexpression or mutation and plays an important role in the development of some cancers, such as gastrointestinal stromal tumors and mast cell disease, molecular therapies targeting KIT mutations are being developed. In acute myeloid leukemia (AML), genome profiling via next-generation sequencing has shown that several genes that are mutated in patients with AML impact patients’ prognosis. Moreover, it was suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML patients. This paper presents (1) previous studies regarding the role of KIT mutations in AML, (2) the data in AML with KIT mutations from the HM-SCREEN-Japan-01 study, a genome profiling study for patients newly diagnosed with AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory AML, and (3) new therapies targeting KIT mutations, such as tyrosine kinase inhibitors and heat shock protein 90 inhibitors. In this era when genome profiling via next-generation sequencing is becoming more common, KIT mutations are attractive novel molecular targets in AML.

1. Introduction

KIT is a type-III receptor tyrosine kinase that contributes to signal transduction in certain cells, such as hematopoietic stem cells, mast cells, and Cajal cells of the gastrointestinal tract [1]. KIT mutations have been reported in more than 90% of cases of mast cytosis [2,3], 80–85% of cases of gastrointestinal stromal tumor (GIST) [4], 10–20% of cases of melanoma [5,6], and cases of acute myeloid leukemia (AML), especially in core-binding factor (CBF) leukemia [7,8,9,10,11]. In AML, recent studies involving the genome profiling of AML via next-generation sequencing (NGS) showed that some mutated genes (e.g., ASXL1, NPM1, FLT3, TP53, CEBPA, and RUNX1) in patients with AML impacted the prognosis of these patients [12,13,14]. Moreover, recent clinical studies incorporating genomic data into treatment decisions, such as the BEAT AML trial [15], suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML. In this era when NGS genome profiling is becoming more common, KIT mutations are attracting attention as new molecular targets in AML.

2. Structure, Function, and Mutation of KIT

2.1. Structure and Function of KIT

The KIT gene is located on chromosome segment 4q11 in humans and is composed of 21 exons [3,16]. The structure of KIT consists of five immunoglobulin-like (Ig-like) domains (D1-D2-D3-D4-D5), a trans-membrane domain (TMD), a juxta-membrane domain (JMD), two kinase domains (KD), and a kinase insert that lies between the KDs [17] (Figure 1A). KIT is expressed on the cell surface and functions as a receptor. The first three Ig-like domains (D1-D3) bind the stem cell factor (SCF), and the two KIT monomers are adjacent to each other. After that, the interaction between D4-D4 and D5-D5 occurs between adjacent KIT monomers, and a stable homodimer is formed. It generates trans-phosphorylation in the JMD region, kinase insert region, KD, and COOH-terminal tail (Figure 1B) [3,18,19]. The signals transmitted by KIT activation are primarily mediated through the phosphatidylinositol 3-kinase (P13K) pathway [20,21], Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway [22,23,24], MAPK pathway [25,26,27], and the Src family kinase pathway [26,28] (Figure 1C). In the hematopoietic system, KIT is strongly expressed in hematopoietic stem cells and progenitor cells [29]. KIT plays an important role in the self-renewal potency of hematopoietic stem cells and differentiation into myeloid and lymphoid cells [30,31]. The expression of KIT is observed to decrease with the differentiation of hematopoietic cells [32]; however, it is highly expressed in mast cells [33].

2.2. Mutations of KIT in Cancer

Both the downregulation and upregulation of KIT signaling have been reported in human cancers. In many cancers, such as GIST, mast cytosis, and AML, the activation of KIT was detected through overexpression or mutation [34]. Moreover, the downregulation of KIT signaling was detected in melanoma [35]. KIT mutations often occur in the membrane proximal immunoglobulin-like domain (exon 8 and exon 9), the JMD (exon 11), and the tyrosine kinase domain (exon 17) [36]. Mutations in the JMD of KIT have been described in GIST [37] and extranodal NK/T cell lymphoma (ENKL) [38]. Mutations in the tyrosine kinase domain of KIT are detected frequently in systemic mastocytosis (SM) [39,40], ENKL [38], and seminomas [41] (Table 1).

3. Prognosis of AML with KIT Mutations Treated with Conventional Chemotherapy

KIT mutations are detected in approximately 4–6% of adult patients with de novo AML [13,42] and 20–40% of adult patients with de novo CBF-AML [7,8,9,10,11]. Fan et al. reported that 256 patients (23%) had KIT mutations in 1123 children with CBF-AML [43]. Three mutational hot-spots (exon 8, exon 10–11, and exon 17) have been identified in the KIT gene [44,45,46,47] (Table 2). Of these, exon 17 has been recognized as the site of KIT mutations most strongly associated with poor prognosis in adult patients with de novo AML harboring RUNX1-RUNX1T1 [7,11,48,49]. Ishikawa et al. showed that KIT exon-17 mutations were associated with poor prognoses in patients with de novo AML with RUNX1-RUNX1T1 being treated with an HDAC regimen [49].
Several reasons have been proposed for the poor prognosis in AML with RUNX1-RUNX1T1 harboring a KIT mutation. For instance, it has been reported that activated KIT cooperates with a C-terminal truncated variant of RUNX1T1 to expand the pool of human CD34+ hematopoietic progenitors and augment the DNA repair machinery, resulting in increased chemo-resistance [50]. Using an in vitro model, Omori et al. compared the cell-proliferative and anti-apoptotic activity of KIT-D816V and KIT-N822K, both of which have been shown to undergo autophosphorylation in the absence of growth factors. Cells harboring KIT-D816V exhibited the activation of the SRC kinase and JAK/STAT pathways and demonstrated greater cell-proliferative and anti-apoptotic ability than cells harboring KIT-N822K [51]. In another study, Tarlock et al. used a cell line harboring a KIT mutation in an in vitro functional analysis, confirming the results of a clinical study of pediatric CBF-AML [52]. Those authors showed that KIT exon-17 mutations resulted in aberrant KIT phosphorylation and were associated with worse clinical outcomes. They further reported that KIT exon-8 mutations have no functional or prognostic impact.

4. KIT Mutation in Unfit and Relapsed/Refractory AML: Results from the HM-SCREEN-Japan-01 Study

Hematologic Malignancy (HM)-SCREEN-Japan-01 (UMIN000035233) is a genome profiling study of patients newly diagnosed with adult AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory (R/R) AML [53,54,55] (methods are described in Supplementary Materials). The objective of the present study was to evaluate the frequency and characteristics of cancer-related genomic alterations in patients with AML using a comprehensive genome profiling assay (FoundationOne®Heme (F1H)) and to determine the quality of specimens used in gene analysis. One hundred and eighty-two patients were recruited, and an F1H report was successfully obtained for one hundred and seventy-seven patients [53,55]. We show the subgroup analysis of the HM-SCREEN-Japan-01 dataset focusing on KIT mutations below.

4.1. Frequency of KIT Mutation in Unfit and R/R AML

Of the 177 patients who participated in the study, we identified 15 patients (8.5%) with a KIT mutation. Of the 15 AML patients with a KIT mutation, 6 were registered as unfit AML and 9 as R/R AML. In addition, a total of 17 patients with CBF leukemia (12 AML with RUNX1-RUNX1T1 gene fusion and 5 AML with CBFβ-MYH11 gene fusion) were confirmed via NGS analysis. Eight of the patients had both a KIT mutation and RUNX1-RUNX1T1; these individuals represented 53% of AML with KIT mutation cases and 67% of AML with RUNX1-RUNX1T1 cases. Two patients had both a KIT mutation and CBFβ-MYH11; these individuals represented 13% of AML with KIT mutation cases and 40% of AML with CBFβ-MYH11 cases. Five patients with non-CBF leukemia had a KIT mutation (Figure 2).
Our study showed a high frequency of KIT mutations in R/R or unfit CBF-AML patients compared with the previous studies targeting new-onset CBF-AML (Table 3). Patients’ characteristics and clinical outcomes are described in the Supplementary Materials.

4.2. Landscape of Gene Mutations in the KIT Mutation Cohort

Fourteen of fifteen patients had a mutation in the region encoding the tyrosine kinase domain, resulting in predicted amino acid substitutions such as D816V, D816F, and N822K (Figure 3A). Two individuals (Patients 39 and 160) had two mutations in the region encoding the kinase domain (Table 4). The median variant allele frequency was 0.25. Chromosomal karyotypes were reported by each investigator. Eight cases were t(8;21)(q22;q22.1), and two were inv(16) or t(16;16). These rearrangements were confirmed via the detection of RUNX1-RUNX1T1 or CBFβ-MYH11, respectively, on NGS analysis. Of the five patients with non-CBF leukemia, two had a complex karyotype, and one had a 3q abnormality (Table 4). The mutation profiles for each case with a KIT mutation are shown in Figure 3B. The proportions of AML with RUNX1-RUNX1T1 among unfit and R/R patients harboring a KIT mutation were 19% (two of six) and 66% (six of nine), respectively. Other than KIT, the mutated gene detected most frequently was RAD21 (3/15, 20%). FLT3, TP53, and GATA2 mutations were found in two cases each (12%). The FLT3 mutations detected in patients 13 and 158 were FLT3-N676K and FLT3-D835H, respectively. The two cases with complex chromosomal abnormalities (patients 13 and 56) both harbored TP53 mutations. In R/R patients, mutations in tyrosine kinase-encoding genes other than KIT (e.g., FLT3 and JAK2) were not detected (Table 4).

4.3. Clinical Impact of KIT Mutation in Unfit and R/R AML

Our data also showed that AML with RUNX1-RUNX1T1 accounted for a very high proportion of unfit and R/R AML patients who had a KIT mutation. Notably, the proportion of AML with RUNX1-RUNX1T1 in R/R patients was 66%. Of the nine R/R patients, none harbored mutations in tyrosine kinase-encoding genes other than KIT, and the number of other gene mutations was similar in patients with and without RUNX1-RUNX1T1 (Figure 3B). Moreover, all of the KIT mutations detected in these nine R/R patients were located in exon 17 (typically encoding D816V/Y/F substitutions in the KIT protein). These data suggested that KIT mutations, especially those in exon 17, are related to a poor prognosis in AML with RUNX1-RUNX1T1, consistent with previous reports on the genetic profiling of R/R AML in patients with de novo AML [7,11,48,49,52].
Based on our analysis of all cases in HM-SCREEN-Japan-01, KIT mutations represented the predictor with the worst outcomes of all assessed gene mutations [53,55]. Most of the surviving patients had received allo-HSCT, regardless of whether they had been diagnosed with CBF or non-CBF leukemia in R/R cases (Supplementary Materials). However, CBF-AML is not currently indicated for transplantation after a first remission [14]. Indeed, there are unmet needs for these R/R patients, such as bridge therapy to transplantation.
In non-CBF leukemia with KIT mutation, three of five patients (Nos. 13, 56, and 111) had high-risk chromosomal abnormalities such as complex events or 3q abnormalities. An additional patient (No. 149) harbored t(3;3)(p25;q13), the source of which was unclear but might be related to the 3q abnormality. Although this subset of patients is small in number, these observations raise the interesting question of whether KIT mutations are associated with an elevated risk of chromosomal abnormality in non-CBF leukemia.
The results obtained from our study are limited by the small number of the KIT-mutated cases, and the results should be confirmed by increasing the total number of patients with AML including KIT-mutated AML. However, previous studies and our results suggested that the treatment strategies with conventional chemotherapy may not be able to overcome KIT-mutation-positive AML. Thus, new treatment agents targeting cancers with KIT mutations are needed.

5. Possible Role for Kinase Inhibitors in the Treatment of AML with KIT Mutation

Few specific inhibitors of KIT have been reported; however, several agents designed to target other RTKs such as FLT and ABL are expected to have utility for KIT mutations [56,57] (Table 5). Several drugs have been used in clinical trials in AML with KIT expression or KIT mutation.
Imatinib (IM), which inhibits ABL, KIT, and PDGFR, has been used in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, and chronic eosinophilic leukemia with PDGFRα rearrangement. In a phase I study, a combination of cytarabine, daunorubicin, and IM was investigated in relapsed AML patients with KIT expression [58]. The complete remission (CR)/CR with incomplete platelet recovery (CRp) rate was 57%. In addition, the phase I/II study evaluated IM combined with mitoxantrone, etoposide, and cytarabine therapy for patients with R/R KIT-positive AML [59]. The combination was well tolerated up to 400 mg/day IM. Of the 21 patients treated at this dose, 13 (62%) achieved CR. Low-dose cytarabine (LDAC) and IM were well tolerated in incompatible or R/R AML patients with KIT expression [60]. However, the combination of LDAC and IM was not shown to be effective compared to LDAC monotherapy. Recently, it was reported that IM as maintenance therapy after the completion of post-remission therapy may improve the outcome of newly diagnosed AML patients [61].
Dasatinib is a medication that is expected to target cancers harboring KIT mutations [52,62,63]. Tarlock et al. showed that cells with KIT exon-17 mutations exhibited in vitro sensitivity to dasatinib [52]. In other work, Malani et al. obtained drug response profiles for established AML cell lines and ex vivo samples from patients with AML by subjecting the cells to high-throughput drug sensitivity and resistance testing with 290 approved and investigational oncology compounds [63]. They suggested that the gene-expression-based upregulation of the KIT pathway may serve as a biomarker of dasatinib efficacy in AML. Indeed, several clinical studies have examined the use of dasatinib for the treatment of CBF leukemia with a KIT mutation. For instance, in single-arm studies by the Cancer and Leukemia Group B (CALGB), patients with CBF leukemia received combination treatment with dasatinib and chemotherapy including HDAC [64]. The results of that study showed that patients harboring tumors with a KIT mutation had disease-free survival and overall survival comparable to those observed for patients harboring tumors with wild-type KIT [64]. Separately, in the phase Ib/IIa study of the German–Austrian AML Study Group (AMLSG), dasatinib was added to intensive induction/consolidation chemotherapy and administered as a maintenance treatment for CBF leukemia [65]. The exploratory analysis of the KIT mutation in that trial showed that five of nine patients who exhibited KIT mutation in paired samples from the time of diagnosis and relapse had lost the variant at relapse, suggesting the possibility that dasatinib inhibited clones with KIT mutations.
Midostaurin is a first-generation FLT3 inhibitor that inhibits FLT3-ITD and TKD mutations [66]. It was reported that the KIT-D816V receptor expressed in Ba/F3 cells was sensitive to midostaurin [48]. A therapeutic effect of midostaurin is expected in KIT D816V mutation-positive mastocytosis [67,68]. A phase II study (MIDOKIT study: NCT01830361) has been conducted to investigate the additional effect of midostaurin on the treatment of t(8; 21) AML with KIT or FLT3-ITD mutations, and its results are awaited.

6. HSP90 Inhibitors for the Treatment of AML with KIT Mutation

Heat shock protein 90 (HSP90) is a molecular chaperone that plays an important role in mediating the correct folding and functionality of its client proteins in cells [69,70]. HSP90 is involved in the stabilization of the cancer-related proteins necessary for tumor development, including receptor tyrosine kinases, signal transducers, cell-cycle regulators, and transcription factors [71,72]. Therefore, HSP90 inhibitors have been developed and are undergoing clinical trials in various cancers. One mechanism of HSP90 inhibitors is blocking the binding of ATP, which induces the degradation of target proteins [71,73,74] (Figure 4). In AML, it has been reported that HSP90 inhibitors may suppress mutated FLT3, as well as the JAK-STAT and P13K pathways [75,76,77]. Yu et al. reported that the inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin disrupted downstream signaling pathways of mutant KIT in a RUNX1-RUNX1T1 with a KIT-mutant cell line [78]. Tsujimura et al. examined the potency of the novel KIT inhibitor KI-328 against different types of mutant KIT kinases in AML. They reported that KI-328 showed little potency against D816V-KIT; however, they demonstrated that HSP90 inhibitors suppress the growth of D816V-KIT-expressing cells [79]. Although these reports suggested the effect of HSP90 inhibitors on AML, the clinical use of HSP90 inhibitors has been delayed, partly due to their association with adverse events such as hepatotoxicity and visual abnormalities [72,74].
Pimitespib (TAS-116), a highly selective inhibitor of HSP90 α and β, is a new agent that is attracting attention for the treatment of malignancies with KIT mutations. HSP90 regulates the conformation, function, and activation of several HSP90 client proteins, including KIT [80,81]. In a mouse model, pimitespib showed anti-tumor activities while minimizing the adverse effects (e.g., visual disturbances) observed with other HSP90 inhibitors [72]. Pimitespib prolonged progression-free survival in a phase III trial comparing the efficacy and safety of pimitespib to a placebo in patients with previously treated GIST [82]. Recently, it was reported that pimitespib exhibits anti-adult T-cell leukemia/lymphoma (ATL) effects in ex vivo and in vivo preclinical models [74]. In this study, pimitespib suppressed the growth of ATL-related cell lines and primary ATL cells ex vivo and tumors in ATL cell-xenografted mice.

7. Conclusions

Here, we discussed the potential of KIT mutations as molecular targets for treating AML. KIT is a type-III receptor tyrosine kinase that contributes to signal transduction in many pathways, including the P13K, JAK/STAT, MAPK, and Src pathways, in various cells. The KIT mutation plays a central role in various malignant tumors such as GIST and SM, and it is attracting attention as an important molecular target. Treatment with tyrosine kinase inhibitors and HSP90 inhibitors is evolving for these diseases. In AML, it has been noted that the KIT mutation is associated with a poor prognosis in primary CBF leukemia. The HM-SCREEN01 study also showed that AML with RUNX1-RUNX1T1 accounted for a very high proportion of patients with R/R AML with KIT mutations, but this point needs to be confirmed in the future by increasing the study population. Furthermore, with the development of NGS in recent years, the pathological and clinical roles of KIT mutations in AML other than CBF leukemia have also attracted attention. Current treatment strategies may not be able to overcome KIT-mutation-positive AML, and the availability of new precision medicine strategies targeting KIT mutations is eagerly awaited in clinical practice.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms23094694/s1.

Author Contributions

Y.M. was the chief investigator in the trial; all authors were involved in patient accrual and data acquisition; S.K., S.C., D.A., Y.M. and A.G. were responsible for data analysis and interpretation; S.K., S.C., Y.M. and A.G. were responsible for the preparation and writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

S.K. declares no competing financial interests. Y.M. received research funding from Ono and received honoraria from Bristol-Myers Squibb, Novartis, and Pfizer. This paper was supported by a National Cancer Research and Development expenses grant.

Institutional Review Board Statement

This study was approved by the Institutional Review Board (IRB) of the National Cancer Center Hospital East and by the IRBs of the individual participating institutions.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study. Written, informed consent to publish this paper was obtained from each patient.

Data Availability Statement

Data sharing not applicable.

Conflicts of Interest

Y.M.: Bristol-Myers Squibb, Novartis Pharma KK, Pfizer Japan, Inc., Takeda (Honoraria). H.S.: Astellas, Teijin, Shionogi, Taiho, Eisai, Celgene, Ono, Takeda, Merck Sharp & Dohme, Sumitomo Dainippon, Nippon Shinyaku, Novartis, Janssen, Chugai, AbbVie (Research Funding); Eisai, Ono, Takeda, Sumitomo Dainippon, Nippon Shinyaku, Daiichi Sankyo, Novartis, Janssen, Chugai, Kyowa Kirin, Otsuka, Bristol-Myers Squibb, Pfizer, Fujimoto, AbbVie, AstraZeneca, Sanofi, Mundi Pharma (Honoraria); Eisai, Celgene, Chugai, AbbVie, AstraZeneca (Membership on an entity’s Board of Directors or advisory committees). T.Y.: Otsuka, Pfizer, Abbie, Astellas, Daiichi Sankyo, Solasia Pharma (Research Funding); Ono Pharmaceutical, Pfizer, Chugai (Honoraria). K.Y.: AbbVie, Astra-Zeneca, Bayer, Celgene, Chugai, Eisai, IQIVA/Incyte, Gilead Sciences, MSD, Mundipharma, Nippon Shinyaku, Novartis, Ono, Otsuka, Solasia Pharma, SymBio, Takeda, Yakult, Zenyaku (Research Funding); AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, IQIVA/HUYA, Janssen, Kyowa Kirin, Meiji Seika Pharma, Mochida, MSD, Mundipharma, Nippon Shinyaku, Novartis, Ono, Otsuka, Pfizer, Sanofi, Sumitomo Dainippon, Takeda (Honoraria); AbbVie, Astra-Zeneca, Celgene, Chugai, Eisai, Daiichi Sankyo, HUYA, Meiji Seika Pharma, MSD, Mundipharma, Ono, Otsuka, Stemline Therapeutics, Takeda (Consultancy). J.K.: Bristol-Myers Squibb, Chugai Pharmaceutical, Dainippon Sumitomo Pharma, Daiichi Sankyo, Sanofi, Kyowa Kirin, Otsuka Pharmaceutical, Astellas Pharma, Takeda, Celgene, MSD, Ono Pharmaceutical, Eisai, Sysmex, Pfizer, Nippon Shinyaku, Shionogi, Asahi Kasei, Taiho Pharmaceutical, Fujimoto Pharmaceutical (Research Funding); Bristol-Myers Squibb, Chugai Pharmaceutical, Dainippon Sumitomo Pharma, Daiichi Sankyo, Sanofi, Kyowa Kirin, Otsuka Pharmaceutical, Astellas Pharma, Takeda, Celgene, Abbvie, Ono Pharmaceutical, Eisai, Pfizer, Nippon Shinyaku, Fujimoto Pharmaceutical (Honoraria); Janssen Pharmaceutical KK, Bristol-Myers Squibb, Sanofi, Celgene, Abbvie (Consultancy). K.U.: Astellas, Abbvie, Gilead, Symbio, Daiichi Sankyo, Sumitomo Dainippon, Otsuka, Novartis, Bristol-Myers Squibb, Ono, Janssen, Celgene, Takeda, Nippon Boehringer Ingelheim, Mundipharma, Astellas-Amgen-Biopharma, Nippon Shinyaku, Kyowa Kirin, Pfizer (Research Funding); Astellas, Symbio, Daiichi Sankyo, Otsuka, Novartis, Bristol-Myers Squibb, Ono, Celgene, Nippon Shinyaku, Kyowa Kirin, Alexion, Eisai, MSD, Takeda, PharmaEssentia, Yakult (Speakers Bureau). A.G.: Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD KK, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Bayer Yakuhin, Ltd., Daiichi-Sankyo Co., Ltd., and Nihon Pharmaceutical Co., Ltd. (Research Funding); Novartis Pharma KK, Alexion Pharmaceuticals, Inc., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Daiichi-Sankyo Co., Ltd., Nihon Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Janssen Pharmaceutical KK, Pfizer Japan Inc., and Sanofi KK (Honoraria); PharmaEssentia Japan KK, Chugai Pharmaceutical Co., Alexion Pharmaceuticals, Inc. (Consultancy).

References

  1. Miettinen, M.; Lasota, J. KIT (CD117): A review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl. Immunohistochem. Mol. Morphol. 2005, 13, 205–220. [Google Scholar] [CrossRef]
  2. Shomali, W.; Gotlib, J. The new tool “KIT” in advanced systemic mastocytosis. Hematol. Am. Soc. Hematol. Educ. Program. 2018, 2018, 127–136. [Google Scholar] [CrossRef] [Green Version]
  3. Lennartsson, J.; Rönnstrand, L. Stem cell factor receptor/c-Kit: From basic science to clinical implications. Physiol. Rev. 2012, 92, 1619–1649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Rubin, B.P.; Heinrich, M.C.; Corless, C.L. Gastrointestinal stromal tumour. Lancet 2007, 369, 1731–1741. [Google Scholar] [CrossRef]
  5. Curtin, J.A.; Busam, K.; Pinkel, D.; Bastian, B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 2006, 24, 4340–4346. [Google Scholar] [CrossRef] [PubMed]
  6. Gutiérrez-Castañeda, L.D.; Nova, J.A.; Tovar-Parra, J.D. Frequency of mutations in BRAF, NRAS, and KIT in different populations and histological subtypes of melanoma: A systemic review. Melanoma Res. 2020, 30, 62–70. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Krauth, M.T.; Eder, C.; Alpermann, T.; Bacher, U.; Nadarajah, N.; Kern, W.; Haferlach, C.; Haferlach, T.; Schnittger, S. High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: Frequency and impact on clinical outcome. Leukemia 2014, 28, 1449–1458. [Google Scholar] [CrossRef] [PubMed]
  8. Qin, Y.Z.; Zhu, H.H.; Jiang, Q.; Jiang, H.; Zhang, L.P.; Xu, L.P.; Wang, Y.; Liu, Y.R.; Lai, Y.Y.; Shi, H.X.; et al. Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: A comprehensive large-scale study from a single Chinese center. Leuk. Res. 2014, 38, 1435–1440. [Google Scholar] [CrossRef] [PubMed]
  9. Allen, C.; Hills, R.K.; Lamb, K.; Evans, C.; Tinsley, S.; Sellar, R.; O’Brien, M.; Yin, J.L.; Burnett, A.K.; Linch, D.C.; et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia 2013, 27, 1891–1901. [Google Scholar] [CrossRef]
  10. Paschka, P.; Du, J.; Schlenk, R.F.; Gaidzik, V.I.; Bullinger, L.; Corbacioglu, A.; Späth, D.; Kayser, S.; Schlegelberger, B.; Krauter, J.; et al. Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): A study of the German-Austrian AML Study Group (AMLSG). Blood 2013, 121, 170–177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Kim, H.J.; Ahn, H.K.; Jung, C.W.; Moon, J.H.; Park, C.H.; Lee, K.O.; Kim, S.H.; Kim, Y.K.; Kim, H.J.; Sohn, S.K.; et al. KIT D816 mutation associates with adverse outcomes in core binding factor acute myeloid leukemia, especially in the subgroup with RUNX1/RUNX1T1 rearrangement. Ann. Hematol. 2013, 92, 163–171. [Google Scholar] [CrossRef] [PubMed]
  12. Papaemmanuil, E.; Gerstung, M.; Bullinger, L.; Gaidzik, V.I.; Paschka, P.; Roberts, N.D.; Potter, N.E.; Heuser, M.; Thol, F.; Bolli, N.; et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N. Engl. J. Med. 2016, 374, 2209–2221. [Google Scholar] [CrossRef] [PubMed]
  13. Ley, T.J.; Miller, C.; Ding, L.; Raphael, B.J.; Mungall, A.J.; Robertson, A.; Hoadley, K.; Triche, T.J., Jr.; Laird, P.W.; Baty, J.D.; et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 2013, 368, 2059–2074. [Google Scholar] [PubMed] [Green Version]
  14. Döhner, H.; Estey, E.; Grimwade, D.; Amadori, S.; Appelbaum, F.R.; Büchner, T.; Dombret, H.; Ebert, B.L.; Fenaux, P.; Larson, R.A.; et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017, 129, 424–447. [Google Scholar] [CrossRef] [Green Version]
  15. Burd, A.; Levine, R.L.; Ruppert, A.S.; Mims, A.S.; Borate, U.; Stein, E.M.; Patel, P.; Baer, M.R.; Stock, W.; Deininger, M.; et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: Feasibility and preliminary efficacy of the Beat AML Master Trial. Nat. Med. 2020, 26, 1852–1858. [Google Scholar] [CrossRef]
  16. Yee, N.S.; Hsiau, C.W.; Serve, H.; Vosseller, K.; Besmer, P. Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3′-kinase, and protein kinase C. J. Biol. Chem. 1994, 269, 31991–31998. [Google Scholar] [CrossRef]
  17. Yuzawa, S.; Opatowsky, Y.; Zhang, Z.; Mandiyan, V.; Lax, I.; Schlessinger, J. Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell 2007, 130, 323–334. [Google Scholar] [CrossRef] [Green Version]
  18. Sattler, M.; Salgia, R. Targeting c-Kit mutations: Basic science to novel therapies. Leuk. Res. 2004, 28 (Suppl. 1), S11–S20. [Google Scholar] [CrossRef]
  19. Pathania, S.; Pentikäinen, O.T.; Singh, P.K. A holistic view on c-Kit in cancer: Structure, signaling, pathophysiology and its inhibitors. Biochim. Biophys. Acta Rev. Cancer 2021, 1876, 188631. [Google Scholar] [CrossRef]
  20. Rottapel, R.; Reedijk, M.; Williams, D.E.; Lyman, S.D.; Anderson, D.M.; Pawson, T.; Bernstein, A. The Steel/W transduction pathway: Kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor. Mol. Cell Biol. 1991, 11, 3043–3051. [Google Scholar]
  21. Serve, H.; Hsu, Y.C.; Besmer, P. Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells. J. Biol. Chem. 1994, 269, 6026–6030. [Google Scholar] [CrossRef]
  22. Weiler, S.R.; Mou, S.; DeBerry, C.S.; Keller, J.R.; Ruscetti, F.W.; Ferris, D.K.; Longo, D.L.; Linnekin, D. JAK2 is associated with the c-kit proto-oncogene product and is phosphorylated in response to stem cell factor. Blood 1996, 87, 3688–3693. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Gotoh, A.; Takahira, H.; Mantel, C.; Litz-Jackson, S.; Boswell, H.S.; Broxmeyer, H.E. Steel factor induces serine phosphorylation of Stat3 in human growth factor-dependent myeloid cell lines. Blood 1996, 88, 138–145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Zhao, S.; Zoller, K.; Masuko, M.; Rojnuckarin, P.; Yang, X.O.; Parganas, E.; Kaushansky, K.; Ihle, J.N.; Papayannopoulou, T.; Willerford, D.M.; et al. JAK2, complemented by a second signal from c-kit or flt-3, triggers extensive self-renewal of primary multipotential hemopoietic cells. Embo J. 2002, 21, 2159–2167. [Google Scholar] [CrossRef] [Green Version]
  25. Wandzioch, E.; Edling, C.E.; Palmer, R.H.; Carlsson, L.; Hallberg, B. Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines. Blood 2004, 104, 51–57. [Google Scholar] [CrossRef] [PubMed]
  26. Lennartsson, J.; Blume-Jensen, P.; Hermanson, M.; Pontén, E.; Carlberg, M.; Rönnstrand, L. Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction. Oncogene 1999, 18, 5546–5553. [Google Scholar] [CrossRef] [Green Version]
  27. Thömmes, K.; Lennartsson, J.; Carlberg, M.; Rönnstrand, L. Identification of Tyr-703 and Tyr-936 as the primary association sites for Grb2 and Grb7 in the c-Kit/stem cell factor receptor. Biochem. J. 1999, 341 Pt 1, 211–216. [Google Scholar] [CrossRef]
  28. Voytyuk, O.; Lennartsson, J.; Mogi, A.; Caruana, G.; Courtneidge, S.; Ashman, L.K.; Rönnstrand, L. Src family kinases are involved in the differential signaling from two splice forms of c-Kit. J. Biol. Chem. 2003, 278, 9159–9166. [Google Scholar] [CrossRef] [Green Version]
  29. Edling, C.E.; Hallberg, B. c-Kit—A hematopoietic cell essential receptor tyrosine kinase. Int. J. Biochem. Cell Biol. 2007, 39, 1995–1998. [Google Scholar] [CrossRef]
  30. Ogawa, M.; Matsuzaki, Y.; Nishikawa, S.; Hayashi, S.; Kunisada, T.; Sudo, T.; Kina, T.; Nakauchi, H.; Nishikawa, S. Expression and function of c-kit in hemopoietic progenitor cells. J. Exp. Med. 1991, 174, 63–71. [Google Scholar] [CrossRef]
  31. Bowie, M.B.; Kent, D.G.; Copley, M.R.; Eaves, C.J. Steel factor responsiveness regulates the high self-renewal phenotype of fetal hematopoietic stem cells. Blood 2007, 109, 5043–5048. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Shin, J.Y.; Hu, W.; Naramura, M.; Park, C.Y. High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias. J. Exp. Med. 2014, 211, 217–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Cruse, G.; Metcalfe, D.D.; Olivera, A. Functional deregulation of KIT: Link to mast cell proliferative diseases and other neoplasms. Immunol. Allergy Clin. N. Am. 2014, 34, 219–237. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Heinrich, M.C.; Blanke, C.D.; Druker, B.J.; Corless, C.L. Inhibition of KIT tyrosine kinase activity: A novel molecular approach to the treatment of KIT-positive malignancies. J. Clin. Oncol. 2002, 20, 1692–1703. [Google Scholar] [CrossRef]
  35. Montone, K.T.; van Belle, P.; Elenitsas, R.; Elder, D.E. Proto-oncogene c-kit expression in malignant melanoma: Protein loss with tumor progression. Mod. Pathol. 1997, 10, 939–944. [Google Scholar] [PubMed]
  36. Liang, J.; Wu, Y.L.; Chen, B.J.; Zhang, W.; Tanaka, Y.; Sugiyama, H. The C-kit receptor-mediated signal transduction and tumor-related diseases. Int. J. Biol. Sci. 2013, 9, 435–443. [Google Scholar] [CrossRef]
  37. Hirota, S.; Isozaki, K.; Moriyama, Y.; Hashimoto, K.; Nishida, T.; Ishiguro, S.; Kawano, K.; Hanada, M.; Kurata, A.; Takeda, M.; et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998, 279, 577–580. [Google Scholar] [CrossRef]
  38. Hongyo, T.; Li, T.; Syaifudin, M.; Baskar, R.; Ikeda, H.; Kanakura, Y.; Aozasa, K.; Nomura, T. Specific c-kit mutations in sinonasal natural killer/T-cell lymphoma in China and Japan. Cancer Res. 2000, 60, 2345–2347. [Google Scholar]
  39. Nagata, H.; Worobec, A.S.; Oh, C.K.; Chowdhury, B.A.; Tannenbaum, S.; Suzuki, Y.; Metcalfe, D.D. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc. Natl. Acad. Sci. USA 1995, 92, 10560–10564. [Google Scholar] [CrossRef] [Green Version]
  40. Longley, B.J.; Tyrrell, L.; Lu, S.Z.; Ma, Y.S.; Langley, K.; Ding, T.G.; Duffy, T.; Jacobs, P.; Tang, L.H.; Modlin, I. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: Establishment of clonality in a human mast cell neoplasm. Nat. Genet. 1996, 12, 312–314. [Google Scholar] [CrossRef]
  41. Tian, Q.; Frierson, H.F., Jr.; Krystal, G.W.; Moskaluk, C.A. Activating c-kit gene mutations in human germ cell tumors. Am. J. Pathol. 1999, 154, 1643–1647. [Google Scholar] [CrossRef] [Green Version]
  42. Patel, J.P.; Gönen, M.; Figueroa, M.E.; Fernandez, H.; Sun, Z.; Racevskis, J.; Van Vlierberghe, P.; Dolgalev, I.; Thomas, S.; Aminova, O.; et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012, 366, 1079–1089. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Fan, J.; Gao, L.; Chen, J.; Hu, S. Influence of KIT mutations on prognosis of pediatric patients with core-binding factor acute myeloid leukemia: A systematic review and meta-analysis. Transl. Pediatr. 2020, 9, 726–733. [Google Scholar] [CrossRef]
  44. Paschka, P.; Döhner, K. Core-binding factor acute myeloid leukemia: Can we improve on HiDAC consolidation? Hematol. Am. Soc. Hematol. Educ. Program. 2013, 2013, 209–219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Ishikawa, Y. Molecular pathogenesis and treatment of core binding factor-acute myeloid leukemia. Jpn. J. Clin. Hematol. 2018, 59, 1997–2006. [Google Scholar]
  46. Kim, S.Y.; Kang, J.J.; Lee, H.H.; Kang, J.J.; Kim, B.; Kim, C.G.; Park, T.K.; Kang, H. Mechanism of activation of human c-KIT kinase by internal tandem duplications of the juxtamembrane domain and point mutations at aspartic acid 816. Biochem. Biophys. Res. Commun. 2011, 410, 224–228. [Google Scholar] [CrossRef] [PubMed]
  47. Berenstein, R. Class III Receptor Tyrosine Kinases in Acute Leukemia—Biological Functions and Modern Laboratory Analysis. Biomark. Insights 2015, 10 (Suppl. 3), 1–14. [Google Scholar] [CrossRef] [Green Version]
  48. Schnittger, S.; Kohl, T.M.; Haferlach, T.; Kern, W.; Hiddemann, W.; Spiekermann, K.; Schoch, C. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006, 107, 1791–1799. [Google Scholar] [CrossRef] [Green Version]
  49. Ishikawa, Y.; Kawashima, N.; Atsuta, Y.; Sugiura, I.; Sawa, M.; Dobashi, N.; Yokoyama, H.; Doki, N.; Tomita, A.; Kiguchi, T.; et al. Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11. Blood Adv. 2020, 4, 66–75. [Google Scholar] [CrossRef]
  50. Wichmann, C.; Quagliano-Lo Coco, I.; Yildiz, Ö.; Chen-Wichmann, L.; Weber, H.; Syzonenko, T.; Döring, C.; Brendel, C.; Ponnusamy, K.; Kinner, A.; et al. Activating c-KIT mutations confer oncogenic cooperativity and rescue RUNX1/ETO-induced DNA damage and apoptosis in human primary CD34+ hematopoietic progenitors. Leukemia 2015, 29, 279–289. [Google Scholar] [CrossRef]
  51. Omori, I.; Yamaguchi, H.; Miyake, K.; Miyake, N.; Kitano, T.; Inokuchi, K. D816V mutation in the KIT gene activation loop has greater cell-proliferative and anti-apoptotic ability than N822K mutation in core-binding factor acute myeloid leukemia. Exp. Hematol. 2017, 52, 56–64.e4. [Google Scholar] [CrossRef] [PubMed]
  52. Tarlock, K.; Alonzo, T.A.; Wang, Y.C.; Gerbing, R.B.; Ries, R.; Loken, M.R.; Pardo, L.; Hylkema, T.; Joaquin, J.; Sarukkai, L.; et al. Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia. Clin. Cancer Res. 2019, 25, 5038–5048. [Google Scholar] [CrossRef] [PubMed]
  53. Hosono, N.; Yamauchi, T.; Chi, S.; Fukushima, K.; Shibayama, H.; Katagiri, S.; Gotoh, A.; Eguchi, M.; Morishita, T.; Ogasawara, R.; et al. Hematologic Malignancies (HM)-Screen-Japan 01: A Mutation Profiling Multicenter Study on Patients with Acute Myeloid Leukemia. Blood 2021, 138 (Suppl. 1), 4457. [Google Scholar] [CrossRef]
  54. Miyamoto, K.; Minami, Y. Precision medicine and novel molecular target therapies in acute myeloid leukemia: The background of hematologic malignancies (HM)-SCREEN-Japan 01. Int. J. Clin. Oncol. 2019, 24, 893–898. [Google Scholar] [CrossRef] [Green Version]
  55. Katagiri, S.; Akahane, D.; Gotoh, A.; Chi, S.; Fukushima, K.; Shibayama, H.; Hosono, N.; Yamauchi, T.; Eguchi, M.; Morishita, T.; et al. Genomic Analysis Focusing on RUNX1-RUNX1T1 in Japanese Patients with AML: HM-Screen-Japan 01. Blood 2021, 138 (Suppl. 1), 4464. [Google Scholar] [CrossRef]
  56. Carter, J.L.; Hege, K.; Yang, J.; Kalpage, H.A.; Su, Y.; Edwards, H.; Hüttemann, M.; Taub, J.W.; Ge, Y. Targeting multiple signaling pathways: The new approach to acute myeloid leukemia therapy. Signal Transduct. Target Ther. 2020, 5, 288. [Google Scholar] [CrossRef]
  57. Klug, L.R.; Corless, C.L.; Heinrich, M.C. Inhibition of KIT Tyrosine Kinase Activity: Two Decades After the First Approval. J. Clin. Oncol. 2021, 39, 1674–1686. [Google Scholar] [CrossRef]
  58. Advani, A.S.; Tiu, R.; Saunthararajah, Y.; Maciejewski, J.; Copelan, E.A.; Sobecks, R.; Sekeres, M.A.; Bates, J.; Rush, M.L.; Tripp, B.; et al. A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia. Leuk. Res. 2010, 34, 1622–1626. [Google Scholar] [CrossRef]
  59. Brandwein, J.M.; Hedley, D.W.; Chow, S.; Schimmer, A.D.; Yee, K.W.; Schuh, A.C.; Gupta, V.; Xu, W.; Kamel-Reid, S.; Minden, M.D. A phase I/II study of imatinib plus reinduction therapy for c-kit-positive relapsed/refractory acute myeloid leukemia: Inhibition of Akt activation correlates with complete response. Leukemia 2011, 25, 945–952. [Google Scholar] [CrossRef]
  60. Heidel, F.; Cortes, J.; Rücker, F.G.; Aulitzky, W.; Letvak, L.; Kindler, T.; Huber, C.; Döhner, H.; Kantarjian, H.; Fischer, T. Results of a multicenter phase II trial for older patients with c-Kit-positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose Ara-C and Imatinib. Cancer 2007, 109, 907–914. [Google Scholar] [CrossRef]
  61. Advani, A.S.; Tse, W.; Li, H.; Jia, X.; Elson, P.; Cooper, B.; Ali-Osman, F.; Park, J.; Rao, A.V.; Rizzieri, D.A.; et al. A Phase II Trial of Imatinib Mesylate as Maintenance Therapy for Patients with Newly Diagnosed C-kit-positive Acute Myeloid Leukemia. Clin. Lymphoma Myeloma Leuk. 2021, 21, 113–118. [Google Scholar] [CrossRef] [PubMed]
  62. Welch, J.S. Expanding dasatinib beyond KIT in acute myeloid leukemia. Haematologica 2020, 105, 2708–2710. [Google Scholar] [CrossRef] [PubMed]
  63. Malani, D.; Yadav, B.; Kumar, A.; Potdar, S.; Kontro, M.; Kankainen, M.; Javarappa, K.K.; Porkka, K.; Wolf, M.; Aittokallio, T.; et al. KIT pathway upregulation predicts dasatinib efficacy in acute myeloid leukemia. Leukemia 2020, 34, 2780–2784. [Google Scholar] [CrossRef] [PubMed]
  64. Marcucci, G.; Geyer, S.; Laumann, K.; Zhao, W.; Bucci, D.; Uy, G.L.; Blum, W.; Eisfeld, A.K.; Pardee, T.S.; Wang, E.S.; et al. Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801. Blood Adv. 2020, 4, 696–705. [Google Scholar] [CrossRef] [PubMed]
  65. Paschka, P.; Schlenk, R.F.; Weber, D.; Benner, A.; Bullinger, L.; Heuser, M.; Gaidzik, V.I.; Thol, F.; Agrawal, M.; Teleanu, V.; et al. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia 2018, 32, 1621–1630. [Google Scholar] [CrossRef]
  66. Weisberg, E.; Boulton, C.; Kelly, L.M.; Manley, P.; Fabbro, D.; Meyer, T.; Gilliland, D.G.; Griffin, J.D. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002, 1, 433–443. [Google Scholar] [CrossRef] [Green Version]
  67. Gotlib, J.; Berubé, C.; Growney, J.D.; Chen, C.C.; George, T.I.; Williams, C.; Kajiguchi, T.; Ruan, J.; Lilleberg, S.L.; Durocher, J.A.; et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 2005, 106, 2865–2870. [Google Scholar] [CrossRef] [Green Version]
  68. Gleixner, K.V.; Mayerhofer, M.; Aichberger, K.J.; Derdak, S.; Sonneck, K.; Böhm, A.; Gruze, A.; Samorapoompichit, P.; Manley, P.W.; Fabbro, D.; et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: Comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood 2006, 107, 752–759. [Google Scholar] [CrossRef] [Green Version]
  69. Miyata, Y.; Nakamoto, H.; Neckers, L. The therapeutic target Hsp90 and cancer hallmarks. Curr. Pharm. Des. 2013, 19, 347–365. [Google Scholar] [CrossRef]
  70. Banerji, U. Heat shock protein 90 as a drug target: Some like it hot. Clin. Cancer Res. 2009, 15, 9–14. [Google Scholar] [CrossRef] [Green Version]
  71. Solárová, Z.; Mojžiš, J.; Solár, P. Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (review). Int. J. Oncol. 2015, 46, 907–926. [Google Scholar] [PubMed] [Green Version]
  72. Ohkubo, S.; Kodama, Y.; Muraoka, H.; Hitotsumachi, H.; Yoshimura, C.; Kitade, M.; Hashimoto, A.; Ito, K.; Gomori, A.; Takahashi, K.; et al. TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol. Cancer Ther. 2015, 14, 14–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Prodromou, C.; Roe, S.M.; O’Brien, R.; Ladbury, J.E.; Piper, P.W.; Pearl, L.H. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 1997, 90, 65–75. [Google Scholar] [CrossRef] [Green Version]
  74. Ikebe, E.; Shimosaki, S.; Hasegawa, H.; Iha, H.; Tsukamoto, Y.; Wang, Y.; Sasaki, D.; Imaizumi, Y.; Miyazaki, Y.; Yanagihara, K.; et al. TAS-116 (pimitespib), a heat shock protein 90 inhibitor, shows efficacy in preclinical models of adult T-cell leukemia. Cancer Sci. 2022, 113, 684–696. [Google Scholar] [CrossRef]
  75. Walsby, E.J.; Lazenby, M.; Pepper, C.J.; Knapper, S.; Burnett, A.K. The HSP90 inhibitor NVP-AUY922-AG inhibits the PI3K and IKK signalling pathways and synergizes with cytarabine in acute myeloid leukaemia cells. Br. J. Haematol. 2013, 161, 57–67. [Google Scholar] [CrossRef]
  76. Al Shaer, L.; Walsby, E.; Gilkes, A.; Tonks, A.; Walsh, V.; Mills, K.; Burnett, A.; Rowntree, C. Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling. Br. J. Haematol. 2008, 141, 483–493. [Google Scholar] [CrossRef]
  77. Minami, Y.; Kiyoi, H.; Yamamoto, Y.; Yamamoto, K.; Ueda, R.; Saito, H.; Naoe, T. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 2002, 16, 1535–1540. [Google Scholar] [CrossRef] [Green Version]
  78. Yu, W.; Wang, J.; Jin, J.; Qian, W.; Qian, J.; Cheng, Y.; Wang, L. Heat shock protein 90 inhibition results in altered downstream signaling of mutant KIT and exerts synergistic effects on Kasumi-1 cells when combining with histone deacetylase inhibitor. Leuk. Res. 2011, 35, 1212–1218. [Google Scholar] [CrossRef]
  79. Tsujimura, A.; Kiyoi, H.; Shiotsu, Y.; Ishikawa, Y.; Mori, Y.; Ishida, H.; Toki, T.; Ito, E.; Naoe, T. Selective KIT inhibitor KI-328 and HSP90 inhibitor show different potency against the type of KIT mutations recurrently identified in acute myeloid leukemia. Int. J. Hematol. 2010, 92, 624–633. [Google Scholar] [CrossRef]
  80. Workman, P.; Burrows, F.; Neckers, L.; Rosen, N. Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann. N. Y. Acad. Sci. 2007, 1113, 202–216. [Google Scholar] [CrossRef]
  81. Saito, Y.; Takahashi, T.; Obata, Y.; Nishida, T.; Ohkubo, S.; Nakagawa, F.; Serada, S.; Fujimoto, M.; Ohkawara, T.; Nishigaki, T.; et al. TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours. Br. J. Cancer 2020, 122, 658–667. [Google Scholar] [CrossRef] [PubMed]
  82. Honma, Y.; Kurokawa, Y.; Sawaki, A.; Naito, Y.; Iwagami, S.; Baba, H.; Komatsu, Y.; Nishida, T.; Doi, T. Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG). J. Clin. Oncol. 2021, 39 (Suppl. 15), 11524. [Google Scholar]
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Figure 1. (A) Schematic representation of the structure of KIT. (B) The homodimeric state of KIT brought about by SCF binding and stabilized by interactions between immunoglobulin-like domains. (C) Signaling pathways involving KIT. The MAPK pathway, JAK/STAT pathway, P13K pathway, and Src family kinase pathway are shown as orange, yellow, green, and blue lines, respectively.
Figure 1. (A) Schematic representation of the structure of KIT. (B) The homodimeric state of KIT brought about by SCF binding and stabilized by interactions between immunoglobulin-like domains. (C) Signaling pathways involving KIT. The MAPK pathway, JAK/STAT pathway, P13K pathway, and Src family kinase pathway are shown as orange, yellow, green, and blue lines, respectively.
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Figure 2. Venn diagram for frequency of KIT mutations and CBF leukemia in HM-SCREEN-Japan-01 [53,54,55]. Red, blue, and green circles indicate the number of patients with AML who harbored KIT mutation, CBFβ-MYH11, and RUNX1-RUNX1T1, respectively. Fifteen had the KIT mutation, eight of whom had RUNX1-RUNX1T1 and two had CBFβ-MYH11.
Figure 2. Venn diagram for frequency of KIT mutations and CBF leukemia in HM-SCREEN-Japan-01 [53,54,55]. Red, blue, and green circles indicate the number of patients with AML who harbored KIT mutation, CBFβ-MYH11, and RUNX1-RUNX1T1, respectively. Fifteen had the KIT mutation, eight of whom had RUNX1-RUNX1T1 and two had CBFβ-MYH11.
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Figure 3. (A) Details of KIT mutation locations detected in HM-SCREEN-Japan-01 [53,54,55]. A total of 17 KIT mutations were detected in 15 cases. (B) Mutational data of the 15 patients with KIT mutations.
Figure 3. (A) Details of KIT mutation locations detected in HM-SCREEN-Japan-01 [53,54,55]. A total of 17 KIT mutations were detected in 15 cases. (B) Mutational data of the 15 patients with KIT mutations.
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Figure 4. HSP90 inhibitor treatment for leukemia (such as FLT3). By binding of the HsP90 inhibitor to the ATP/ADP pocket of Hsp90, the equilibrium state of Hsp90 becomes ADP dominant. This inhibits the function of chaperone complexes containing client proteins and promotes the degradation of client proteins.
Figure 4. HSP90 inhibitor treatment for leukemia (such as FLT3). By binding of the HsP90 inhibitor to the ATP/ADP pocket of Hsp90, the equilibrium state of Hsp90 becomes ADP dominant. This inhibits the function of chaperone complexes containing client proteins and promotes the degradation of client proteins.
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Table
Table 1. Summary of KIT mutations in cancers.
Table 1. Summary of KIT mutations in cancers.
SiteExonDiseaseDescription
Immunoglobulin-like domain8AMLT417, Y418, D419
9GISTA502
MastocytosisK5091
Trans-membrane domain10AMLV530I
MastocytosisF522C, A533D
Juxta-membrane domain11AMLV560, V559, ITD
GISTCD117, V559A, V559D, W557R, V560G
MelanomaL576P
MastocytosisV560G
13AMLK642E
MelanomaK642E
14GISTK704, N705
Kinase insert15GISTS715
Kinase domain16AML1748T, L773S
17AMLD816V, D816Y, D816F, D816H, N822, V8251
Germ cell tumorD816H, D816V
MastocytosisD816V, D816Y, D816H, D820G
ENKLV825A, D816N
Abbreviations: AML: acute myeloid leukemia, GIST: gastrointestinal stromal tumor, ENKL: extranodal NK/T cell lymphoma.
Table
Table 2. Summary of KIT mutations in AML.
Table 2. Summary of KIT mutations in AML.
ExonDescriptionFunctional Impact
8T417, Y418, D419Hyper-reactivity to stem cell factor
10–11V530, V540, W557, V559, L576, ITDSpontaneous dimer formation
17D816, D820, N822, Y823, V825Auto activation
Abbreviations: AML: acute myeloid leukemia.
Table
Table 3. Frequency of KIT mutations in CBF-AML.
Table 3. Frequency of KIT mutations in CBF-AML.
Author, YearDisease StatusFrequency of KIT Mutations
CBF LeukemiaRUNX1-RUNX1T1CBFβ-MYH11
Qin 2014Newly diagnosed37% (128/351)39% (99/253)30% (29/98)
Allen 2013Newly diagnosed28% (100/354)23% (46/199)35% (54/155)
Kim 2013Newly diagnosed26% (32/121)27% (22/82)35% (54/155)
Ishikawa 2019Newly diagnosed34% (63/199)32% (42/132)31% (21/67)
HM-SCREEN01R/R or Unfit59% (10/17)67% (8/12)40% (2/5)
Abbreviations: CBF: core-binding factor, R/R: relapse/refractory.
Table
Table 4. Summary of KIT mutations and chromosomal karyotypes.
Table 4. Summary of KIT mutations and chromosomal karyotypes.
KIT Mutation
IDCategoryDescriptionSNVVAFOther MutationsChromosomal Karyotype
13UnfitD816V2447A > T0.372FLT3, KRAS, CEBPA, TP53Complex karyotype
50UnfitD816V2447A > T0.123RAD21, SPENt(8;21)(q22;q22.1)
56UnfitD816F2446_2447GA > TT0.37TP53, CDKN2A, CDKN2BComplex karyotype
149UnfitD816V2447A > T0.344ASXL1, DNMT3A, SETBP1, FANCD2, CASP846, XY, t(3;3)(p25:q13)
158UnfitT417_D419 > Y1249_1255ACTTACG > T0.078FLT3, NRASinv(16)/t(16;16)
160UnfitD816V2447A > T0.146CSF3R, JAK1t(8;21)(q22;q22.1)
N822K2466T > G0.018
10R/RD816V2447A > T0.234Nonet(8;21)(q22;q22.1)
39R/RD816V2447A > T0.252RAD21t(8;21)(q22;q22.1)
D816Y2446G > T0.056
45R/RD816Y2446G > T0.923CD36t(8;21)(q22;q22.1)
76R/RD816V2447A > T0.932NF1t(8;21)(q22;q22.1)
94R/RD816V2447A > T0.459RAD21, NPM1Normal
111R/RD816V2447A > T0.338SETD23q Abnormality
121R/RD816Y2446G > T0.021CBLinv(16)/t(16;16)
146R/RD816V2447A > T0.082GATA2, HIST1H2BJt(8;21)(q22;q22.1)
175R/RN822K2466T > G0.461GATA2, PHF6, ATMt(8;21)(q22;q22.1)
Abbreviations: R/R: relapse/refractory, SNV: single-nucleotide variant, VAF: variant allele frequency.
Table
Table 5. Summary of FDA-approved KIT-targeted therapies.
Table 5. Summary of FDA-approved KIT-targeted therapies.
DrugPrimary TargetsFDA-Approved Disease
ImatinibBCR-ABL1CML, Ph+ALL, HES, GIST, SM, DFSP
DasatinibBCR-ABL1CML, PhALL
SunitinibVEGFR and FLT3GIST, RCC, Pancreatic Cancer
RegorafenibVEGFRGIST, HCC, Colorectal Cancer
MidostaurinFLT3AML (FLT3 mutation), SM
RipretinibKITGIST
AvapritinibKIT/PDGFRAGIST, SM
Abbreviations: FDA: US Food and Drug Administration, CML: chronic myeloid leukemia, PhALL: Philadelphia-positive acute lymphoblastic leukemia, HES: chronic eosinophilic leukemia with PDGFRα rearrangement, GIST: gastrointestinal stromal tumor, SM: systemic mastocytosis, DFSP: dermatofibrosarcoma protuberans, RCC: renal cell carcinoma, HCC: hepatocellular carcinoma.
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Katagiri, S.; Chi, S.; Minami, Y.; Fukushima, K.; Shibayama, H.; Hosono, N.; Yamauchi, T.; Morishita, T.; Kondo, T.; Yanada, M.; et al. Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia. Int. J. Mol. Sci. 2022, 23, 4694. https://doi.org/10.3390/ijms23094694

AMA Style

Katagiri S, Chi S, Minami Y, Fukushima K, Shibayama H, Hosono N, Yamauchi T, Morishita T, Kondo T, Yanada M, et al. Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia. International Journal of Molecular Sciences. 2022; 23(9):4694. https://doi.org/10.3390/ijms23094694

Chicago/Turabian Style

Katagiri, Seiichiro, SungGi Chi, Yosuke Minami, Kentaro Fukushima, Hirohiko Shibayama, Naoko Hosono, Takahiro Yamauchi, Takanobu Morishita, Takeshi Kondo, Masamitsu Yanada, and et al. 2022. "Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia" International Journal of Molecular Sciences 23, no. 9: 4694. https://doi.org/10.3390/ijms23094694

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