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

Cancer Lett. 2020 Jan 28;469:410-418. doi: 10.1016/j.canlet.2019.11.005. Epub 2019 Nov 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Rearrangement / genetics
  • Genetic Heterogeneity*
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Mice
  • Mutation / genetics
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Survival Rate

Substances

  • KMT2A protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase