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

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.

Non‐leukemic pediatric mixed phenotype acute leukemia/lymphoma: Genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma

“…Our results remain limited by the small number of cases, which simply reflects the rarity of the disease. Certainly, larger scale molecular characterizations in leukemic MPAL allow much more insight into the biology and prognostic subgroups as recently demonstrated . Nevertheless, this study might influence oncological treatment decisions in the way that treatment by a chemotherapy protocol proven effective in precursor lymphoblastic lymphomas also seems to be effective in these mixed phenotype neoplasms.…”

“…Therefore, we excluded the diagnosis of tissue infiltration by a tissue manifestation/myelosarcoma of an acute myeloid leukemia with t(8;21)(q22;q22) in these cases. In a very recent genomic study on over 150 cases of pediatric MPALs diagnosed by flow cytometry, two new principal subgroups of MPAL were described, that is, a T‐myeloid and a B‐myeloid subtype, the former with recurrent biallelic WT1 alterations, the latter with recurrent ZNF384 rearrangement . The data reported by Alexander et al in addition, support a concept that founding molecular lesions in MPALs arise in early progenitor cells and prime these for lineage aberrancy and diversity, thus rendering MPAL a separable group from other lymphoblastic and/or myeloid neoplasias.…”

“…In a very recent genomic study on over 150 cases of pediatric MPALs diagnosed by flow cytometry, two new principal subgroups of MPAL were described, that is, a T‐myeloid and a B‐myeloid subtype, the former with recurrent biallelic WT1 alterations, the latter with recurrent ZNF384 rearrangement . The data reported by Alexander et al in addition, support a concept that founding molecular lesions in MPALs arise in early progenitor cells and prime these for lineage aberrancy and diversity, thus rendering MPAL a separable group from other lymphoblastic and/or myeloid neoplasias. Unfortunately, due to limited material in our tissue‐based cases, we did not screen for these specific genomic alterations nor can comment on molecular evolution in our series.…”

“…Unfortunately, due to limited material in our tissue‐based cases, we did not screen for these specific genomic alterations nor can comment on molecular evolution in our series. Moreover, the study by Alexander et al describes overlapping molecular features between the new provisional WHO‐subtype of early‐T‐cell precursor acute lymphoblastic leukemia (WHO 2017) with the T‐myeloid MPALs. Cases 8 and 11 of our cohort (Table ) might be candidates for this group, nevertheless case 11 did not express CD34, a typical marker of the early‐T‐cell precursor leukemias …”

Mixed phenotype acute leukaemia with predominant myeloid blasts and a small subset of B/myeloid blasts shares the same mutation profile

“…Recent advances in understanding the molecular pathology of MPALs has provided some insight into MPAL leukaemogenesis. A recent study provided evidence for the model that MPALs originate from a haematopoietic stem cell that acquires founding genetic lesions including ones that enable phenotypic plasticity (Alexander et al , ). Sequencing blast subpopulations in multiple cases of MPAL allowed demonstrating that phenotypically distinct blasts shared somatic genetic mutations and DNA methylation profiles.…”