Nat Genet. 2019 Apr;51(4):694-704. doi: 10.1038/s41588-019-0375-1. Epub 2019 Mar 29.
Genomic subtyping and therapeutic targeting of acute erythroleukemia.
Iacobucci I1, Wen J1, Meggendorfer M2, Choi JK1, Shi L3, Pounds SB3, Carmichael CL4, Masih KE1, Morris SM1, Lindsley RC5, Janke LJ1, Alexander TB6, Song G1, Qu C1, Li Y7, Payne-Turner D1, Tomizawa D8, Kiyokawa N9, Valentine M10, Valentine V10, Basso G11,12, Locatelli F13,14, Enemark EJ15, Kham SKY16, Yeoh AEJ16,17, Ma X7, Zhou X7, Sioson E7, Rusch M7, Ries RE18, Stieglitz E19, Hunger SP20, Wei AH4,21,22, To LB23,24, Lewis ID24, D'Andrea RJ25, Kile BT26,27, Brown AL25,28, Scott HS25,28, Hahn CN25,28, Marlton P29, Pei D3, Cheng C3, Loh ML19, Ebert BL5, Meshinchi S18, Haferlach T2, Mullighan CG30.
Abstract
Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives 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 high-risk leukemia.
- PMID:
- 30926971
- DOI:
- 10.1038/s41588-019-0375-1
No comments:
Post a Comment