Integrative genomic analysis identifies multiple subtypes and therapeutic targets in acute erythroid leukemia

Acute erythroid leukemia (AEL) is a high risk leukemia of poorly understood genetic basis, and controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic and clinical features of 159 childhood and adult AEL cases to non-AEL myeloid disorders, and identified patterns of mutation that describe 5 age-related subgroups with distinct transcriptional profiles: adult, TP53-mutated; NPM1-mutated; KMT2A-mutated/rearranged; adult, DDX41-mutated; and pediatric, NUP98-rearranged. Mutational spectra were age-dependent and significantly associated with outcome, with NPM1 mutations and high HOXB9 expression being associated with favorable prognosis, and TP53, FLT3 and RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases, and include recurrent mutations of ALK and NTRK1, the latter of which drive erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this form of leukemia that has hitherto and dismal outcome.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

3 Datasets 2 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003412	None	Illumina HiSeq 2000	152
EGAD00001003413	None	Illumina HiSeq 2000	145
EGAD00010001443	SNP array	Affymetrix SNP6.0	154

Publications	Citations
Genomic subtyping and therapeutic targeting of acute erythroleukemia. Iacobucci I, Wen J, Meggendorfer M, Choi JK, Shi L, Pounds SB, Carmichael CL, Masih KE, Morris SM, Lindsley RC, Janke LJ, Alexander TB, Song G, Qu C, Li Y, Payne-Turner D, Tomizawa D, Kiyokawa N, Valentine M, Valentine V, Basso G, Locatelli F, Enemark EJ, Kham SKY, Yeoh AEJ, Ma X, Zhou X, Sioson E, Rusch M, Ries RE, Stieglitz E, Hunger SP, Wei AH, To LB, Lewis ID, D'Andrea RJ, Kile BT, Brown AL, Scott HS, Hahn CN, Marlton P, Pei D, Cheng C, Loh ML, Ebert BL, Meshinchi S, Haferlach T, Mullighan CG. Nat Genet 51: 2019 694-704	67
Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication. Liu Y, Klein J, Bajpai R, Dong L, Tran Q, Kolekar P, Smith JL, Ries RE, Huang BJ, Wang YC, Alonzo TA, Tian L, Mulder HL, Shaw TI, Ma J, Walsh MP, Song G, Westover T, Autry RJ, Gout AM, Wheeler DA, Wan S, Wu G, Yang JJ, Evans WE, Loh M, Easton J, Zhang J, Klco JM, Meshinchi S, Brown PA, Pruett-Miller SM, Ma X. Nat Commun 14: 2023 1739	3

Publications

Citations

Genomic subtyping and therapeutic targeting of acute erythroleukemia.
Iacobucci I, Wen J, Meggendorfer M, Choi JK, Shi L, Pounds SB, Carmichael CL, Masih KE, Morris SM, Lindsley RC, Janke LJ, Alexander TB, Song G, Qu C, Li Y, Payne-Turner D, Tomizawa D, Kiyokawa N, Valentine M, Valentine V, Basso G, Locatelli F, Enemark EJ, Kham SKY, Yeoh AEJ, Ma X, Zhou X, Sioson E, Rusch M, Ries RE, Stieglitz E, Hunger SP, Wei AH, To LB, Lewis ID, D'Andrea RJ, Kile BT, Brown AL, Scott HS, Hahn CN, Marlton P, Pei D, Cheng C, Loh ML, Ebert BL, Meshinchi S, Haferlach T, Mullighan CG. Nat Genet 51: 2019 694-704

Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.
Liu Y, Klein J, Bajpai R, Dong L, Tran Q, Kolekar P, Smith JL, Ries RE, Huang BJ, Wang YC, Alonzo TA, Tian L, Mulder HL, Shaw TI, Ma J, Walsh MP, Song G, Westover T, Autry RJ, Gout AM, Wheeler DA, Wan S, Wu G, Yang JJ, Evans WE, Loh M, Easton J, Zhang J, Klco JM, Meshinchi S, Brown PA, Pruett-Miller SM, Ma X. Nat Commun 14: 2023 1739