Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse

Abstract

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.

Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ

“…Recently, Dnmt3a has attracted much attention, as it is one of the most frequently mutated genes in cancer (Kim et al, 2013), especially in acute myeloid leukemia (Garg et al, 2015; Ley et al, 2010). In fact, a loss-of-function mutation of Dnmt3a is one of the earliest mutations that occurs in human acute myeloid leukemia (Shlush et al, 2014).…”

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

“…Homozygous loss-of-function mutations in IDH3B have been found in two families with retinitis pigmentosa (49), and somatic mutations in IDH3B have been recently found in acute myelogenous leukemia (50). IDH3B encodes the beta subunit of NADspecific isocitrate dehydrogenase 3 (IDH3), which is involved in the oxidation of isocitrate to a-ketoglutarate in the Krebs cycle.…”

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

“…FLT3 mutations are identified in about one-third of adult (AML) (69,70). FLT3 mutations induce constitutive activation of phosphoinositide 3-kinase (PI3K)-AKT, RAS-MEK-mitogen-activated protein kinase (MAPK), and signal transducers and activators of transcription (STAT) five pathways, leading uncontrolled cell proliferation, blockage of differentiation and cell survival (52).…”