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Author Notes:

Correspondence and requests for materials should be addressed to C.M. or H.I. harles.mullighan@stjude.org; hiroto.inaba@stjude.org.

See publication for full list of authors.

T.B.A.: study design, flow analysis and sorting, data analysis, and manuscript writing.

Z.G.: genomic data analysis.

I.I.: genomic and mouse experiments, data analysis, data interpretation and manuscript preparation.

K.D.: ZNF384r modeling.

J.K.C.: central review of immunophenotype.

B.X.: ChIP–seq and RNA-seq data analysis.

D.P.-T and H.Y.: performed experiments.

M.L.L. and S.P.H.: led and contributed to Children’s Oncology Group ALL studies and the ALL TARGET project.

M.B. and B.W.: reviewed flow cytometry.

M.D., N.A.H., and A.C.: provided clinical data.

J.H., E.O., B.B, G.B., S.E., V.d.H., C.M.Z., A.Y., D.R., D.T., N.K., T.L., B.D.M., D.C., H.H., A.M., A.S.M., O.H., K.E.N., J.R.D., and J.Z.: patient samples and clinical data.

S.M.: data for comparison cohort.

Y.-L.Y.: flow analysis.

M.A.S., T.M.D., L.C.H., P.G., M.A.M., Y.M., A.J.M., R.A.M., S.J.M.J., and J.M.G.A.: genomic sequencing, analysis, and support.

M.V.: performed FISH.

L.J.J.: necropsy and histology on xenograft models.

J.E.R. and C.-H.P.: patient samples and clinical data.

D.S.G.: support for genomic analysis and manuscript editing.

L.D. and Y.L.: genomic analysis.

X.C., L.S., S.P. and D.P.: statistical analysis.

S.N.: somatic and germline variant analysis.

H.I.: acquisition of patient samples and clinical data.

C.G.M.: designed and oversaw the study, analysed data and wrote the manuscript.

These authors contributed equally: Thomas B. Alexander, Zhaohui Gu, Ilaria Iacobucci.

We thank the Biorepository, the Genome Sequencing Facility of the Hartwell Center for Bioinformatics and Biotechnology, and the Flow Cytometry and Cell Sorting core facility and Cytogenetics core facility of St. Jude Children’s Research Hospital (SJCRH).

We acknowledge Canada’s Michael Smith Genome Sciences Centre, Vancouver, Canada for library construction and sequencing.

The authors declare no competing interests.


Research Funding:

This work was supported in part by the American Lebanese Syrian Associated Charities of SJCRH, Cookies for Kids Cancer (to H.I.), St. Baldrick’s Foundation Robert J. Arceci Innovation Award and Henry Schueler 41&9 Foundation (to C.G.M.), SJCRH Physician Scientist Training Program Fellowship (to T.B.A.), the National Cancer Institute grants P30 CA021765 (SJCRH Cancer Center Support Grant), Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (to the COG Statistical Center), U24 CA114766 (to COG; Specimen Banking), and Outstanding Investigator Award R35 CA197695 (to C.G.M.).

This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract No. HHSN261200800001E (to C.G.M. and Michael Smith Genome Sciences Centre).


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics

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

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Journal Title:



Volume 562, Number 7727


, Pages 373-+

Type of Work:

Article | Post-print: After Peer Review


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.

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