KMT2A rearranged acute lymphoblastic leukaemia: unravelling the genomic complexity and heterogeneity of this high-risk disease
Date
2019
Authors
Forgione, M.O.
McClure, B.J.
Eadie, L.N.
Yeung, D.T.
White, D.L.
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Journal article
Citation
Cancer Letters, 2019; 469:410-418
Statement of Responsibility
Michelle O.Forgione, Barbara J.McClure, Laura N.Eadie, David T.Yeung, Deborah L.White
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Abstract
KMT2A rearranged (KMT2Ar) acute lymphoblastic leukaemia (ALL) is a high-risk genomic subtype, with long-term survival rates of less than 60% across all age groups. These cases present a complex clinical challenge, with a high incidence in infants, high-risk clinical features and propensity for aggressive relapse. KMT2A rearrangements are highly pathogenic leukaemic drivers, reflected by the high incidence of KMT2Ar ALL in infants, who carry few leukaemia-associated cooperative mutations. However, transgenic murine models of KMT2Ar ALL typically exhibit long latency and mature or mixed phenotype, and fail to recapitulate the aggressive disease observed clinically. Next-generation sequencing has revealed that KMT2Ar ALL also occurs in adolescents and adults, and potentially cooperative genomic lesions such as PI3K-RAS pathway variants are present in KMT2Ar patients of all ages. This review addresses the aetiology of KMT2Ar ALL, with a focus on the cell of origin and mutational landscape, and how genomic profiling of KMT2Ar ALL patients in the era of next-generation sequencing demonstrates that KMT2Ar ALL is a complex heterogenous disease. Ultimately, understanding the underlying biology of KMT2Ar ALL will be important in improving long-term outcomes for these high-risk patients.
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Crown Copyright © 2019 Published by Elsevier B.V. All rights reserved.