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Genomic subtyping and therapeutic targeting of acute erythroleukemia

by Alexander, Thomas B. , Kham, Shirley K. Y. , Brown, Anna L. , Song, Guangchun , Locatelli, Franco , Wei, Andrew H. , Cheng, Cheng , Morris, Sarah M. , Hahn, Christopher N. , Ma, Xiaotu , Ries, Rhonda E. , Ebert, Benjamin L. , Carmichael, Catherine L. , Scott, Hamish S. , Kiyokawa, Nobutaka , Lewis, Ian D. , D’Andrea, Richard J. , Qu, Chunxu , Enemark, Eric J. , Meggendorfer, Manja , Kile, Benjamin T. , Pei, Deqing , Haferlach, Torsten , Iacobucci, Ilaria , Shi, Lei , Tomizawa, Daisuke , Janke, Laura J. , Loh, Mignon L. , Mullighan, Charles G. , Basso, Giuseppe , To, L Bik , Pounds, Stanley B. , Lindsley, R. Coleman , Rusch, Michael , Payne-Turner, Debbie , Meshinchi, Soheil , Wen, Ji , Stieglitz, Elliot , Marlton, Paula , Zhou, Xin , Masih, Katherine E. , Choi, John K. , Li, Yongjin , Yeoh, Allen E. J. , Hunger, Stephen P. , Valentine, Marcus , Sioson, Edgar , Valentine, Virginia

in 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

2019

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Genomic subtyping and therapeutic targeting of acute erythroleukemia

2019

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2019

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Journal Article

Genomic subtyping and therapeutic targeting of acute erythroleukemia

Alexander, Thomas B.,

Kham, Shirley K. Y.,

Brown, Anna L.,

Song, Guangchun,

Locatelli, Franco,

Wei, Andrew H.,

Cheng, Cheng,

Morris, Sarah M.,

Hahn, Christopher N.,

Ma, Xiaotu,

Ries, Rhonda E.,

Ebert, Benjamin L.,

Carmichael, Catherine L.,

Scott, Hamish S.,

Kiyokawa, Nobutaka,

Lewis, Ian D.,

D’Andrea, Richard J.,

Qu, Chunxu,

Enemark, Eric J.,

Meggendorfer, Manja,

Kile, Benjamin T.,

Pei, Deqing,

Haferlach, Torsten,

Iacobucci, Ilaria,

Shi, Lei,

Tomizawa, Daisuke,

Janke, Laura J.,

Loh, Mignon L.,

Mullighan, Charles G.,

Basso, Giuseppe,

To, L Bik,

Pounds, Stanley B.,

Lindsley, R. Coleman,

Rusch, Michael,

Payne-Turner, Debbie,

Meshinchi, Soheil,

Wen, Ji,

Stieglitz, Elliot,

Marlton, Paula,

Zhou, Xin,

Masih, Katherine E.,

Choi, John K.,

Li, Yongjin,

Yeoh, Allen E. J.,

Hunger, Stephen P.,

Valentine, Marcus,

Sioson, Edgar,

Valentine, Virginia

2019

Overview

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.

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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

631/67/1990/283

/ 631/67/1990/283/1897

/ Acute leukemia

/ Adolescent

/ Adult

/ Adults

/ Age