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Cancer Lett. 2019 Nov 6. pii: S0304-3835(19)30560-9. doi: 10.1016/j.canlet.2019.11.005. [Epub ahead of print]

KMT2A rearranged acute lymphoblastic leukaemia: Unravelling the genomic complexity and heterogeneity of this high-risk disease.

Author information

1
Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia; School of Biological Sciences, University of Adelaide, SA, 5000, Australia. Electronic address: Michelle.Forgione@sahmri.com.
2
Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia; Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, 5000, Australia.
3
Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia; Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, 5000, Australia; Department of Haematology, Royal Adelaide Hospital, SA, 5000, Australia.
4
Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia; School of Biological Sciences, University of Adelaide, SA, 5000, Australia; Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, 5000, Australia; Australian Genomics Health Alliance (AGHA), The Murdoch Children's Research Institute, Parkville, Vic, 3052, Australia; Australian and New Zealand Children's Oncology Group (ANZCHOG), Clayton, Vic, 3168, Australia.

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.

KEYWORDS:

Adult acute lymphoblastic leukaemia; KMT2A; Leukaemia aetiology; MLL; Mixed lineage leukaemia

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