Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

Abstract

BACKGROUND Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.)

Aberrant hnRNP K expression: All roads lead to cancer

“…[19][20][21]23 Furthermore, TCGA recently demonstrated that HNRNPK mutations have the capacity to act as driving events in AML. 22 However, it is currently unknown if these HNRNPK mutations confer gain-of-function or haploinsufficient phenotypes.…”

“…[14][15][16][17][18] In contrast, other clinical studies suggest reduced hnRNP K expression, due to deletion of or mutations in the HNRNPK gene, may underpin the pathogenesis of acute myeloid leukemia (AML). [19][20][21][22][23] In the case of mutation, there are further questions concerning whether specific mutations inactivate the protein or potentially stabilize or confer gain-of-function phenotypes, reminiscent of mutations observed in the c-Myc protein and mutant p53 proteins, respectively.…”

Epigenetic alterations in acute myeloid leukemias

“…Mutations of cohesin are found in several forms of cancer. On the basis of the report from the genome atlas research network,~13% of AML cases have mutations in cohesin complex components, and these mutations have been mainly found in patients with M1 and M2 FAB subtypes [95]. There is some evidence that alterations of the cohesin complex are initiating events in leukemogenesis [96].…”

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

“…Normal hematopoietic cell differentiation and proliferation are regulated by the expression and interaction of specific transcription factors (1,2), which are altered in AML (3)(4)(5). Elucidation of the genomic landscape of AML has further highlighted that alterations in myeloid transcription factors play a significant role in leukemogenesis (4). Recent attention has focused on the role of aberrant expression of the Krüppel-like factor (KLF) family of transcription factors in cancer (5).…”