The genetic basis and cell of origin of mixed phenotype acute leukaemia

Nature. 2018 Oct;562(7727):373-379. doi: 10.1038/s41586-018-0436-0. Epub 2018 Sep 12.

Abstract

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Lineage / genetics
  • DNA Mutational Analysis
  • Female
  • Genetic Variation / genetics
  • Genome, Human / genetics
  • Genomics
  • Humans
  • Immunophenotyping
  • Leukemia, Biphenotypic, Acute / classification
  • Leukemia, Biphenotypic, Acute / genetics*
  • Leukemia, Biphenotypic, Acute / pathology*
  • Male
  • Models, Genetic
  • Mutation / genetics
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Trans-Activators / genetics

Substances

  • Trans-Activators
  • ZNF384 protein, human