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An Allele-specific Gene Expression Assay to Test the Functional Basis of Genetic Associations
Published on: November 3, 2010
The genetic basis and cell of origin of mixed phenotype acute leukaemia
Thomas B Alexander1,2, Zhaohui Gu3, Ilaria Iacobucci3
1Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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.
Insights
Mixed phenotype acute leukaemia (MPAL) subtypes are genetically distinct, with unique alterations in T/myeloid and B/myeloid MPAL. These findings reveal the cell of origin and founding lesions drive MPAL, informing future clinical trials.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Mixed phenotype acute leukaemia (MPAL) is a high-risk leukemia with myeloid and lymphoid features.
- MPAL presents challenges due to limited genetic characterization and therapeutic consensus.
Purpose of the Study:
- To genetically characterize the two principal subtypes of MPAL: T/myeloid (T/M) and B/myeloid (B/M).
- To investigate the origins of MPAL's immunophenotypic heterogeneity and its relationship to genetic alterations.
Main Methods:
- Comparative genomic analysis of T/M and B/M MPAL subtypes.
- Investigation of somatic genetic variation and its impact on immunophenotypic heterogeneity.
- Analysis of founding lesions and cell of origin in MPAL development.
Main Results:
- T/M MPAL and B/M MPAL are genetically distinct subtypes.
- ZNF384 rearrangement is common in B/M MPAL; biallelic WT1 alterations are prevalent in T/M MPAL.
- Immunophenotypic heterogeneity is independent of somatic genetics, with founding lesions in primitive progenitors.
Conclusions:
- MPAL's lineage promiscuity is driven by the cell of origin and founding lesions, not solely accumulated genomic alterations.
- MPAL fits within the spectrum of immature leukaemias.
- Findings provide a genetic framework for MPAL treatment strategies and clinical trials.
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