Genomic Analysis Provides Insights into Acute Erythroleukemia

Acute erythroleukemia (AEL) is a high-risk subtype of acute myeloid leukemia (AML) with similarities to myelodysplasia that is characterized by the proliferation of erythroid and myeloid blasts in the bone marrow. Unlike other myeloid malignancies, no studies have comprehensively characterized the genomic landscape of AEL. This has complicated AEL diagnosis and therapy, as it is unclear whether AEL patients should receive aggressive induction chemotherapy given to patients with AML or less intensive therapy for myelodysplastic syndrome (MDS). Iacobucci and colleagues extensively profiled a cohort of 159 AEL cases spanning the age spectrum from pediatric to older adult cases to better distinguish AEL from AML and MDS and to identify genomic determinants of outcome. Overall, the mutation spectrum of AEL was intermediate between AML and MDS, suggesting that current classification paradigms that classify some AEL cases as either AML or MDS based on mutational prevalence are not reliable. Comparison of AELs with non-AEL myeloid disorders identified age-related subgroups with district genomic and transcriptional features, with alterations of TP53, KMT2A, DDX41, NPM1, and NUP98 defining distinct groups, and these genomic alterations and gene-expression profiles stratified AEL prognosis better than the existing World Health Organization AEL classification based on percentage of erythroid cells and non-erythroid blasts. Therapeutically actionable mutations were observed in 45% of cases, and previously unreported NTRK1 mutations were identified in 3 AEL cases. Structural modeling and mouse bone marrow transplant assays confirmed the leukemogenicity of these events and their responsiveness to clinically available TRK inhibitors. Collectively, this work suggests a revision of current diagnostic and prognostic criteria for AEL to include genomic alterations and transcriptional signatures and suggests that targeted therapies may have activity in a subset of patients with AEL.

Iacobucci I, Wen J, Meggendorffer M, Choi JK, Shi L, Pounds SB, et al. Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nat Genetics 2019;51:694–704.

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