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

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Nature. Volume 562: p.373-379, 12 September 2018, 10.1038/s41586-018-0436-0

Mixed phenotype acute leukemia (MPAL) is a high-risk subtype of leukemia with myeloid and lymphoid features, limited genetic characterization, and lack of consensus regarding appropriate therapy. We perfomed whole genome and transcriptome sequence and show that the two principal subtypes, T/M and B/M MPAL are genetically distinct. B/M cases commonly harbor rearrangement of ZNF384, and T/M cases are enriched for WT1 alterations, and share similar genomic features with early T-cell precursor acute lymphoblastic leukemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of genetic variation , that founder lesions arise in primitive hematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, primes tumor cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukemias and provide a genetically-informed framework for future clinical trials of MPAL.

The GDC sample list differs from the publication’s by suppression of three aliquots:

  • TARGET-15-SJMPAL040037-09A.3-01D
  • TARGET-15-SJMPAL016342-04A-01D
  • TARGET-15-SJMPAL040032-09A.3-01D

The GDC’s analysis pipeline, which made use of the CalculateContamination module in GATK with a cutoff of 0.04 (4%), identified these three aliquots as being contaminated with material from other patients.

The St. Jude analysis pipeline used pairwise IBD (identity-by-descent) analysis provided by Plink Software to detect cross-sample contamination but then also used customized methods to minimize the effect of the contamination in these samples in the original analysis:

  • For TARGET-15-SJMPAL040037-09A.3-01D and TARGET-15-SJMPAL040032-09A.3-01D, intermediate results showed that the called somatic mutations were enriched with large number of somatic mutations reported in dbSNP, which confirmed cross-patient contamination that was not obvious from IBD analysis. For these two samples, somatic mutations reported in other sub-populations were recorded, but investigators did not report any novel mutations from them.

  • For TARGET-15-SJMPAL016342-04A-01D, the contamination was determined to be marginal by both the intermediate results and IBD analysis, so the standard analysis was performed and some novel somatic mutations were reported from this sample.

The L3 dataset used in this publication can be accessed at the NCI’s Office of Cancer Genomics’ Data Coordination Center via the TARGET Data Matrix at

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