Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia

Abstract

Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor (P ¼ 0.355), but was a factor when using MB-PCR (P ¼ 0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses (P ¼ 0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML.

The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias

“…Thus, Ding and coworkers sequenced the primary leukemia and relapse genomes from eight AML patients allowing to define two major clonal evolution patterns during AML relapse: (i) the clonal evolution of the leukemias is related to the founding clone through the gain of mutations, allowing its transformation into the relapse clone; (ii) the clonal evolution of the tumor is dependent upon a subclone minoritary at diagnosis, surviving to the induction therapy, acquiring new mutations, and expanding at relapse [18]. In t(8; 21) AMLs, a minoritary subpopulation of leukemia cells that harbored c-kit mutations at diagnosis becomes dominant at relapse [19]. Furthermore, a study carried out on a small subset of CD34 + AML patients, mostly with normal karyotype, showed that these AMLs harbor an oligoclonal immature compartment at presentation, with the presence of a minor subpopulation in initial diagnosis samples, but dominating the bulk leukemic blasts at relapse [20].…”

“…The purified residual hematopoietic stem cells were screened for the presence of leukemia-associated mutations and were found to possess some leukemia-associated mutations, such as TET2, NPM1, and SMC1A; however, the FLT3-ITD mutation was not found in these residual hematopoietic stem cells [23]. Considering the total number of mutations (51 mutations) present in leukemic cells, a large part of them (32 mutations) were detectable in nonleukemic hematopoietic stem cells [19]. According to these findings, the residual hematopoietic stem cells have been defined as “preleukemic” stem cells [23].…”

Therapy for metastatic melanoma: the past, present, and future

“…The ligand for KIT is stem cell factor (SCF) and binding of SCF to c-kit induces activation of downstream signaling pathways that are involved in mediating growth and survival signals within the cell including the P13K-AKT-mTOR pathway and the RAS-RAF-MEK-ERK pathway. KIT has been implicated in the pathogenesis of several cancers including acute myeloid leukemia and gastrointestinal stromal tumors (GIST) [46-49]. Unlike in GIST where c-kit mutations tend to be deletions or insertions in exon 11, c-kit mutations in melanoma occur at multiple sites along the gene including both the juxta-membrane domain at exon 11 and exon 13 and the kinase domain at exon 17 and are usually point mutations that do not correlate with KIT copy number or CD117 expression [50,51].…”

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

“…Although the inhibition of the mutated ABL was efficacious to the CML, a substantial number of patients had failed to respond to the ABL inhibitors by developing drug resistance [52]. Src’s pathway [54] and c-kit’s mutation [55] were reported to contribute significantly to the drug resistance, and were the key adverse prognostic and predictive prognosis factors for leukemia [54,55]. Thus, the multi-target drugs inhibiting ABL together with Src or c-Kit were expected to counteract drug resistance of the existing ABL inhibitors.…”