KIT mutations confer a distinct gene expression signature in core binding factor leukaemia

Abstract

Summary Core binding factor (CBF) leukaemias, characterized by either inv(16)(p13.1q22) or t(8;21)(q22;q22), constitute acute myeloid leukaemia (AML) subgroups with favourable prognosis. However, 40–50% of patients relapse, emphasizing the need for risk‐adapted treatment approaches. In this regard, studying secondary genetic aberrations, such as mutations of the KIT gene, is of great interest, particularly as they can be targeted by receptor tyrosine kinase inhibitors (TKI). However, so far little is known about the biology underlying KIT‐mutated CBF leukaemias. We analysed gene expression profiles of 83 CBF AML cases with known KIT mutation status in order to gain novel insights in KIT‐mutated CBF pathogenesis. KIT‐mutated cases were characterized by deregulation of genes belonging to the NFkB signalling complex suggesting impaired control of apoptosis. Notably, a subgroup of KIT wildtype cases was also characterized by the KIT mutation signature due to yet unknown aberrations. Our data suggest that this CBF leukaemia subgroup might profit from TKI therapy, however, the relevance of the KIT mutation‐associated signature remains to be validated prior to clinical implementation. Nevertheless, the existence of such a signature supports the notion of relevant biological differences in CBF leukaemia and might serve as diagnostic tool in the future.

Gene expression profiling in MDS and AML: potential and future avenues

“…24 Similarly, the identification of KIT wild-type core-binding factor AMLs harboring expression profiles similar to KIT-mutated core-binding factors suggests that different leukemogenic events can result in the activation and deregulation of identical sets of genes and/or oncogenic pathways. 25 In accordance, gene expression signatures have been identified that reflect the heterogeneous clinical response of both CN-AML and core-binding factor AML, thereby providing further evidence that GEP-based outcome prediction in AML is feasible and can provide information in addition to cytogenetics and molecular genetics. 22,26 To discover gene expression signatures of prognostic value, a recent proof-of-principle study successfully applied a novel strategy including a combination of supervised and unsupervised data analysis and defined a 133-gene signature.…”

Old and new prognostic factors in acute myeloid leukemia with deranged core‐binding factor beta

“…Recently, Luck et al, showed that KIT mutations confer a distinct gene expression signature in CBF-AML and that one of the most significantly differentially expressed gene is LRP6 that is essential for noncanonical WNT5A signaling and thus for the maintenance of stem and progenitor cells [43,44]. Authors suggested that the different gene profiling may lead to an enhancement of proliferation in the KITmutated cases, which may be reflected in the higher blast counts of those patients [43]. The clinical observations that affected patients with t(8;21) appear to have a higher WBC count and WBC-index at presentation and a higher frequency of EML might support this hypotheses [30,39,45].…”

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

“…25 BRB Array Tools Version 4.2.1 was also used for data analysis using class comparison and pathway class comparison tools as previously described. 26 All tests were two-sided. An effect was considered significant if the p values were 0.05 or less.…”