Acute Myeloid Leukemia Coverage From Every Angle

Identification of Mutational Constellations in AML

By: Lauren Harrison, MS
Posted: Wednesday, March 18, 2020

Researchers performed whole-genome and transcriptome sequencing of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and were able to integrate mutational and expressional data to define subtypes of mutations that have prognostic significance. This work was presented by Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital in Memphis, on behalf of colleagues at the 2019 American Society for Hematology (ASH) Annual Meeting & Exposition (Abstract LBA-04) and published in the journal Blood.

“Our study provides a much richer understanding of [different] subtypes, akin to a dictionary of all the genomic alterations,” stated Dr. Iacobucci in an ASH press release. “It also underscores the value of having comprehensive genomic information at the start of treatment to remove uncertainty and help clinicians better understand a patient’s outlook.”

The team used samples of blood and bone marrow from 1,304 individuals with either AML or MDS. All DNA and RNA from these samples were sequenced and analyzed for somatic and pressured germline-sequence mutations, chimeric fusions, and structural complex variations. The data were then combined with information on health outcomes and physical features of each patient’s cancer.

Sequencing was able to confirm the diagnosis of AML with recurrent abnormalities in 10.9% of patients. These AML cases had a distinct gene-expression profile, carried a good prognosis, and were associated with various clusters of mutations. RUNX1-RUNXT1 leukemia was found to have mutations in KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2; PML-RARA promyelocytic leukemia had mutations in FLT3, DDX54, WT1, and CALR; CBFB-rearranged leukemia had mutations in KIT and BCORL1. Additionally, 9% of cases had rearrangements in KMT2A, which was associated with a poor outcome.

Analysis further identified groups of AML or MDS that lacked cytogenetic abnormalities in which TET2 and DNMT3A were frequently mutated. Genes promoting hematopoiesis were enriched in a group with NPM1 mutations, which occurred in 27.4% of patients with AML. A combination of NPM1 mutations and FLT3 mutations produced a worse outcome than NPM1 mutations alone, whereas mutations in cohesion genes with mutated NPM1 seemed to be associated with a better outcome.

Disclosure: For full disclosures of the study authors, visit

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