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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Vydáno v:	Nature genetics Ročník 51; číslo 4; s. 694 - 704
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.04.2019 Nature Publishing Group
Témata:	631/67/1990/283 631/67/1990/283/1897 Acute leukemia Adolescent Adult Adults Age Agriculture Animal Genetics and Genomics Bioinformatics Biomedical and Life Sciences Biomedicine Bone marrow Cancer genetics Cancer Research 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 Gene Function Genes Genetic aspects Genomes Genomics Genomics - methods Homeodomain Proteins - genetics Human 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 Nucleophosmin p53 Protein Pediatrics Prognosis Risk Subgroups Therapeutic targets Transcription Tumor proteins Tumor Suppressor Protein p53 - genetics Tumors Young Adult
ISSN:	1061-4036, 1546-1718, 1546-1718
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Popis
Shrnutí:	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. Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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