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

Thomas B. Alexander, Zhaohui Gu, Ilaria Iacobucci, Kirsten Dickerson, John K. Choi, Beisi Xu, Debbie Payne-Turner, Hiroki Yoshihara, Mignon L. Loh, John Horan, Barbara Buldini, Giuseppe Basso, Sarah Elitzur, Valerie de Haas, C. Michel Zwaan, Allen Yeoh, Dirk Reinhardt, Daisuke Tomizawa, Nobutaka Kiyokawa, Tim LammensBarbara De Moerloose, Daniel Catchpoole, Hiroki Hori, Anthony Moorman, Andrew S. Moore, Ondrej Hrusak, Soheil Meshinchi, Etan Orgel, Meenakshi Devidas, Michael J Borowitz, Brent Wood, Nyla A. Heerema, Andrew Carrol, Yung Li Yang, Malcolm A. Smith, Tanja M. Davidsen, Leandro C. Hermida, Patee Gesuwan, Marco A. Marra, Yussanne Ma, Andrew J. Mungall, Richard A. Moore, Steven J.M. Jones, Marcus Valentine, Laura J. Janke, Jeffrey E. Rubnitz, Ching Hon Pui, Liang Ding, Yu Liu, Jinghui Zhang, Kim E. Nichols, James R. Downing, Xueyuan Cao, Lei Shi, Stanley Pounds, Scott Newman, Deqing Pei, Jaime M. Guidry Auvil, Daniela S. Gerhard, Stephen P. Hunger, Hiroto Inaba, Charles G. Mullighan

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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.

Original languageEnglish (US)
Pages (from-to)373-379
Number of pages7
JournalNature
Volume562
Issue number7727
DOIs
StatePublished - Oct 1 2018

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ASJC Scopus subject areas

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Alexander, T. B., Gu, Z., Iacobucci, I., Dickerson, K., Choi, J. K., Xu, B., Payne-Turner, D., Yoshihara, H., Loh, M. L., Horan, J., Buldini, B., Basso, G., Elitzur, S., de Haas, V., Zwaan, C. M., Yeoh, A., Reinhardt, D., Tomizawa, D., Kiyokawa, N., ... Mullighan, C. G. (2018). The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature, 562(7727), 373-379. https://doi.org/10.1038/s41586-018-0436-0