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

Distribution of MPAL subtypes by age

Distribution of MPAL subtypes by age. Alexander et al. (2018) Nature.

Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, Payne-Turner D, Yoshihara H, Loh ML, Horan J, Buldini B, Basso G, Elitzur S, de Haas V, Zwaan CM, Yeoh A, Reinhardt D, Tomizawa D, Kiyokawa N, Lammens T, De Moerloose B, Catchpoole D, Hori H, Moorman A, Moore AS, Hrusak O, Meshinchi S, Orgel E, Devidas M, Borowitz M, Wood B, Heerema NA, Carrol A, Yang Y, Smith MA, Davidsen TM, Hermida LC, Gesuwan P, Marra MA, Ma Y, Mungall AJ, Moore RA, Jones SJM, Valentine M, Janke LJ, Rubnitz JE, Pui C, Ding L, Liu Y, Zhang J, Nichols KE, Downing JR, Cao X, Shi L, Pounds S, Newman S, Pei D, Guidry Auvil JM, Gerhard DS, Hunger SP, Inaba H, Mullighan CG


September 12, 2018

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 WT1alterations 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.

Last updated: September 14, 2018