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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.

SUBMITTER: Alexander TB

PROVIDER: S-EPMC6195459 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Alexander Thomas B TB Gu Zhaohui Z Iacobucci Ilaria I Dickerson Kirsten K Choi John K JK Xu Beisi B Payne-Turner Debbie D Yoshihara Hiroki H Loh Mignon L ML Horan John J Buldini Barbara B Basso Giuseppe G Elitzur Sarah S de Haas Valerie V Zwaan C Michel CM Yeoh Allen A Reinhardt Dirk D Tomizawa Daisuke D Kiyokawa Nobutaka N Lammens Tim T De Moerloose Barbara B Catchpoole Daniel D Hori Hiroki H Moorman Anthony A Moore Andrew S AS Hrusak Ondrej O Meshinchi Soheil S Orgel Etan E Devidas Meenakshi M Borowitz Michael M Wood Brent B Heerema Nyla A NA Carrol Andrew A Yang Yung-Li YL Smith Malcolm A MA Davidsen Tanja M TM Hermida Leandro C LC Gesuwan Patee P Marra Marco A MA Ma Yussanne Y Mungall Andrew J AJ Moore Richard A RA Jones Steven J M SJM Valentine Marcus M Janke Laura J LJ Rubnitz Jeffrey E JE Pui Ching-Hon CH Ding Liang L Liu Yu Y Zhang Jinghui J Nichols Kim E KE Downing James R JR Cao Xueyuan X Shi Lei L Pounds Stanley S Newman Scott S Pei Deqing D Guidry Auvil Jaime M JM Gerhard Daniela S DS Hunger Stephen P SP Inaba Hiroto H Mullighan Charles G CG

Nature 20180912 7727

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 leuk ...[more]

PMID: 30209392

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Project description:Mixed-phenotype leukemia (MPAL) is a type of acute leukemia in which the blast population shows mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. MPALs are rare and carry a poor prognosis, thus, often pose both a diagnostic and therapeutic challenge. Conventionally, the diagnosis of MPAL requires either a single blast population with a lineage-defining phenotypic expression of multiple lineages (myeloid, B-cell and/or T-cell) (biphenotypic) or two distinct blast populations that each independently satisfy criteria for designation as AML, B-ALL, and/or T-ALL (bilineage). Given the rarity of MPAL, minimal studies have been performed to describe the genomic landscape of these neoplasms. IRB approval was obtained. Central MCC database was searched for any patient with a diagnosis of acute undifferentiated leukemia (AUL), acute leukemia of ambiguous lineage (ALAL), and MPAL. All patient diagnoses were manually reviewed by a hematopathologist to confirm the diagnosis of MPAL. Genomic and molecular data were collated from the EMR and bioinformatically from MCC genomics repositories. Twenty-eight patients with MPAL were identified. Thirteen were female and 15 were male. Average age was 56 years old (range = 28-81). Ten cases were biclonal and 18 were biphenotypic. Diagnoses were as follows: B/myeloid (n = 18), T/myeloid (n = 9), and T/B (n = 1). Cytogenetic analysis (Karyotype +/- FISH) was available for 27 patients. The most frequent recurrent abnormalities were complex karyotype (n = 8), BCR/ABL1 translocation (n = 6), Del 5q/-5 (n = 4), Polysomy 21 (n = 4). Mutational analysis was available for 18 patients wherein mutations were detected in 45 unique genes. The most frequently mutated genes were TP53 (7), RUNX1 (6), WT1 (4), MLL2 (3), FLT3 (3), CBL (2), ASXL1 (2), TET2 (2), MAP3K6 (2), MLL (2), and MAP3K1 (2). Targetable or potentially targetable biomarkers were found in 56% of cases. Overall survival was 19.5 months (range = 0-70 m). Ten patients were treated with an allogeneic stem cell transplant and had superior outcome (p = 0.0013). In one the largest series of MPAL cases to date, we corroborate previous findings with enriched detection of RUNX1 and FLT3-ITD mutations along with discovery of unreported mutations (MAP3K) that may be amenable to therapeutic manipulation. We also report the frequent occurrence of AML with MDS-related changes (AML-MRC)-defining cytogenetic abnormalities (26%). Finally, we show that those patients that received stem cell transplant had a better overall survival. Our findings support the need to genomically profile MPAL cases to exploit opportunities for targeted therapies in this orphan disease with dismal prognosis.

Dataset Information

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

Publications

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

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