Genomic subtyping and therapeutic targeting of acute erythroleukemia

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 ag...

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Published inNature genetics Vol. 51; no. 4; pp. 694 - 704
Main Authors Iacobucci, Ilaria, Wen, Ji, Meggendorfer, Manja, Choi, John K, Shi, Lei, Pounds, Stanley B, Carmichael, Catherine L, Masih, Katherine E, Morris, Sarah M, Lindsley, R Coleman, Janke, Laura J, Alexander, Thomas B, Song, Guangchun, Qu, Chunxu, Li, Yongjin, Payne-Turner, Debbie, Tomizawa, Daisuke, Kiyokawa, Nobutaka, Valentine, Marcus, Valentine, Virginia, Basso, Giuseppe, Locatelli, Franco, Enemark, Eric J, Kham, Shirley K Y, Yeoh, Allen E J, Ma, Xiaotu, Zhou, Xin, Sioson, Edgar, Rusch, Michael, Ries, Rhonda E, Stieglitz, Elliot, Hunger, Stephen P, Wei, Andrew H, To, L Bik, Lewis, Ian D, D'Andrea, Richard J, Kile, Benjamin T, Brown, Anna L, Scott, Hamish S, Hahn, Christopher N, Marlton, Paula, Pei, Deqing, Cheng, Cheng, Loh, Mignon L, Ebert, Benjamin L, Meshinchi, Soheil, Haferlach, Torsten, Mullighan, Charles G
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.04.2019
Subjects
Acute leukemia
Adolescent
Adult
Adults
Age
Bioinformatics
Bone marrow
Cancer genetics
Cancer therapies
Care and treatment
Cell cycle
Child
Child, Preschool
Children
Classification
Deoxyribonucleic acid
Diagnosis
DNA
DNA methylation
Epigenetics
Erythroleukemia
Female
fms-Like Tyrosine Kinase 3 - genetics
Genes
Genetic aspects
Genomes
Genomics
Genomics - methods
Health risks
Homeodomain Proteins - genetics
Humans
Infant
Infant, Newborn
Leukemia
Leukemia, Erythroblastic, Acute - genetics
Leukemogenesis
Male
Medical prognosis
Medical schools
Mutation
Mutation - genetics
Myelodysplastic syndrome
Myeloid leukemia
Myeloid-Lymphoid Leukemia Protein - genetics
Nuclear Proteins - genetics
p53 Protein
Pediatrics
Prognosis
Risk
Subgroups
Therapeutic targets
Transcription
Tumor proteins
Tumor Suppressor Protein p53 - genetics
Tumors
Young Adult
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Summary: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.
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K.E.M., S.M.M., T.B.A., D.P.T., M.V., V.V. performed experiments. G.S. analyzed copy number data. E.J.E. performed structure modeling. M.M, C.C, D.T., N.K., G.B., F.L., S.K.K.Y., A.Y.E.J., R.E.R., E.S., A.W., L.B.T., I.D.L., R.D.A., B.T.K., A.L.B., H.S., C.H., P.M., S.M., T.H. provided patient samples and clinical data. R.C.L., B.L.E. shared data for the MDS comparison cohort. Y.L., C.Q., X.M., X.Z., E.S., S.P.H, M.R. performed genomic sequencing, analysis, and support. L.S., S.P., D.P., C.C. performed statistical analyses. C.G.M. designed and oversaw the study, analyzed genomic data and wrote the manuscript. All the authors read and approved the final version of the manuscript.
AUTHOR CONTRIBUTIONS
I.I. led the collaboration, coordination and processing of patient samples, analyzed genomic data, performed experiments and wrote the manuscript. J.W. analyzed sequencing data. J.K.C. performed central review of immunophenotypic data. L.J.J. performed histopathology analyses
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-019-0375-1