Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) has been thought to be the consequence of two broad complementation classes of mutations: class I and class II. However, overlap-mutations between them or within the same class and the position of TP53 mutation are not fully analyzed. We comprehensively analyzed the FLT3, cKIT, N-RAS, C/EBPA, AML1, MLL, NPM1, and TP53 mutations in 144 newly diagnosed de novo AML. We found 103 of 165 identified mutations were overlapped with other mutations, and most overlap-mutations consisted of class I and class II mutations. Although overlap-mutations within the same class were found in seven patients, five of them additionally had the other class mutation. These results suggest that most overlap-mutations within the same class might be the consequence of acquiring an additional mutation after the completion both of class I and class II mutations. However, mutated genes overlapped with the same class were limited in N-RAS, TP53, MLL-PTD, and NPM1, suggesting the possibility that these irregular overlap-mutations might cooperatively participate in the development of AML. Notably, TP53 mutation was overlapped with both class I and class II mutations, and associated with morphologic multilineage dysplasia and complex karyotype. The genotype consisting of complex karyotype and TP53 mutation was an unfavorable prognostic factor in entire AML patients, indicating this genotype generates a disease entity in de novo AML. These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation.

Normal bone marrow signal-transduction profiles: a requisite for enhanced detection of signaling dysregulations in AML

“…This is interesting in that c-KIT/CD117 and FLT3 mutations are generally mutually exclusive. 49 In this case, FLT3 mutation analysis was negative. Thus, in all these cases, functionally c-KIT/CD117 and Flt3 receptors are dysregulated regardless of the mutational status.…”

Features of Ras activation by a mislocalized oncogenic tyrosine kinase: FLT3 ITD signals via K-Ras at the plasma membrane of Acute Myeloid Leukemia cells

“…Mutations in FLT3 confer a proliferative advantage and are referred to as 'class I mutations'. In addition to class I mutations, leukemogenesis requires further genetic lesions such as mutations that lead to blocked hematopoietic differentiation ('class II mutations') (Deguchi and Gilliland, 2002;Ishikawa et al, 2009;Cancer Genome Atlas Research Network, 2013). Another group of class I mutations are activating mutations in RAS genes (Fröhling et al, 2005;Tyner et al, 2009).…”

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

“…Although it is likely that an unidentified Class II mutation may exist, this "exception" has been observed in other studies. [16][17] A model utilizing information from the Cancer Genome Atlas recently predicted that NRAS activating mutations would coexist with KIT mutations in hematopoietic malignancies and were, therefore, strong candidates for cosequencing.…”