Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients

Abstract

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

Partial tandem duplication of KMT2A (MLL) may predict a subset of myelodysplastic syndrome with unique characteristics and poor outcome

“…Co-occurrence of FLT3-ITD and MLL-PTD has been reported previously in AML, though the significance of this finding on outcome or response is currently unknown. 15 The potential use of demethylating agents and histone deacetylase inhibitors, as has been proposed for cases of MLL-PTD AML, 3,9 is one area of further exploration. Of note, de novo MLL-PTD AML patients, which exclude patients with underlying MDS, showed the best outcomes of patients in this study, possibly due to early transplantation, and may have better prognosis than has been previously reported.…”

Clinical characteristics and prognosis of acute myeloid leukemia associated with DNA-methylation regulatory gene mutations

“…In recent years, the use of next-generation sequencers has facilitated energetic exploration of gene mutations, leading to the discovery of other AML-related gene mutations, [14][15][16][17] and mutations in the genes that regulate DNA methylation, such as DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase1 (IDH1), and isocitrate dehydrogenase 2 (IDH2). [18][19][20][21][22][23] It has been suggested that these gene mutations may also have prognostic relevance in some cases of AML, but this view has yet to become established.…”

Cell Division Patterns in Acute Myeloid Leukemia Stem-like Cells Determine Clinical Course: A Model to Predict Patient Survival

“…Acute myeloid leukemias (AML) comprise a heterogeneous group of diseases (11)(12). Evidence accumulated that AMLs are maintained by a population of leukemic stem cells (LSC, leukemia initiating cells, leukemia stem-like cells) that are resistant to conventional chemotherapy, and likely are responsible for relapses (7)(8)13).…”