The genetic basis and cell of origin of mixed phenotype acute leukaemia.
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-L
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-H
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
- Publisher:
- Springer Science and Business Media LLC
- Publication Type:
- Journal Article
- Citation:
- Nature, 2018, 562, (7727), pp. 373-379
- Issue Date:
- 2018-10
Closed Access
Filename | Description | Size | |||
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s41586-018-0436-0.pdf | Published version | 15.14 MB | Adobe PDF |
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Alexander, TB | |
dc.contributor.author | Gu, Z | |
dc.contributor.author | Iacobucci, I | |
dc.contributor.author | Dickerson, K | |
dc.contributor.author | Choi, JK | |
dc.contributor.author | Xu, B | |
dc.contributor.author | Payne-Turner, D | |
dc.contributor.author | Yoshihara, H | |
dc.contributor.author | Loh, ML | |
dc.contributor.author | Horan, J | |
dc.contributor.author | Buldini, B | |
dc.contributor.author | Basso, G | |
dc.contributor.author | Elitzur, S | |
dc.contributor.author | de Haas, V | |
dc.contributor.author | Zwaan, CM | |
dc.contributor.author | Yeoh, A | |
dc.contributor.author | Reinhardt, D | |
dc.contributor.author | Tomizawa, D | |
dc.contributor.author | Kiyokawa, N | |
dc.contributor.author | Lammens, T | |
dc.contributor.author | De Moerloose, B | |
dc.contributor.author |
Catchpoole, D |
|
dc.contributor.author | Hori, H | |
dc.contributor.author | Moorman, A | |
dc.contributor.author | Moore, AS | |
dc.contributor.author | Hrusak, O | |
dc.contributor.author | Meshinchi, S | |
dc.contributor.author | Orgel, E | |
dc.contributor.author | Devidas, M | |
dc.contributor.author | Borowitz, M | |
dc.contributor.author | Wood, B | |
dc.contributor.author | Heerema, NA | |
dc.contributor.author | Carrol, A | |
dc.contributor.author | Yang, Y-L | |
dc.contributor.author | Smith, MA | |
dc.contributor.author | Davidsen, TM | |
dc.contributor.author | Hermida, LC | |
dc.contributor.author | Gesuwan, P | |
dc.contributor.author | Marra, MA | |
dc.contributor.author | Ma, Y | |
dc.contributor.author | Mungall, AJ | |
dc.contributor.author | Moore, RA | |
dc.contributor.author | Jones, SJM | |
dc.contributor.author | Valentine, M | |
dc.contributor.author | Janke, LJ | |
dc.contributor.author | Rubnitz, JE | |
dc.contributor.author | Pui, C-H | |
dc.contributor.author | Ding, L | |
dc.contributor.author | Liu, Y | |
dc.contributor.author | Zhang, J | |
dc.contributor.author | Nichols, KE | |
dc.contributor.author | Downing, JR | |
dc.contributor.author | Cao, X | |
dc.contributor.author | Shi, L | |
dc.contributor.author | Pounds, S | |
dc.contributor.author | Newman, S | |
dc.contributor.author | Pei, D | |
dc.contributor.author | Guidry Auvil, JM | |
dc.contributor.author | Gerhard, DS | |
dc.contributor.author | Hunger, SP | |
dc.contributor.author | Inaba, H | |
dc.contributor.author | Mullighan, CG | |
dc.date.accessioned | 2022-09-03T22:23:50Z | |
dc.date.available | 2018-07-03 | |
dc.date.available | 2022-09-03T22:23:50Z | |
dc.date.issued | 2018-10 | |
dc.identifier.citation | Nature, 2018, 562, (7727), pp. 373-379 | |
dc.identifier.issn | 0028-0836 | |
dc.identifier.issn | 1476-4687 | |
dc.identifier.uri | http://hdl.handle.net/10453/161301 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | Springer Science and Business Media LLC | |
dc.relation.ispartof | Nature | |
dc.relation.isbasedon | 10.1038/s41586-018-0436-0 | |
dc.rights | info:eu-repo/semantics/closedAccess | |
dc.subject.classification | General Science & Technology | |
dc.subject.mesh | Cell Lineage | |
dc.subject.mesh | DNA Mutational Analysis | |
dc.subject.mesh | Female | |
dc.subject.mesh | Genetic Variation | |
dc.subject.mesh | Genome, Human | |
dc.subject.mesh | Genomics | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Immunophenotyping | |
dc.subject.mesh | Leukemia, Biphenotypic, Acute | |
dc.subject.mesh | Male | |
dc.subject.mesh | Models, Genetic | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Neoplastic Stem Cells | |
dc.subject.mesh | Phenotype | |
dc.subject.mesh | Trans-Activators | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Trans-Activators | |
dc.subject.mesh | DNA Mutational Analysis | |
dc.subject.mesh | Immunophenotyping | |
dc.subject.mesh | Genomics | |
dc.subject.mesh | Cell Lineage | |
dc.subject.mesh | Phenotype | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Genome, Human | |
dc.subject.mesh | Models, Genetic | |
dc.subject.mesh | Female | |
dc.subject.mesh | Male | |
dc.subject.mesh | Neoplastic Stem Cells | |
dc.subject.mesh | Leukemia, Biphenotypic, Acute | |
dc.subject.mesh | Genetic Variation | |
dc.title | The genetic basis and cell of origin of mixed phenotype acute leukaemia. | |
dc.type | Journal Article | |
utslib.citation.volume | 562 | |
utslib.location.activity | England | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Engineering and Information Technology | |
utslib.copyright.status | closed_access | * |
dc.date.updated | 2022-09-03T22:23:39Z | |
pubs.issue | 7727 | |
pubs.publication-status | Published | |
pubs.volume | 562 | |
utslib.citation.issue | 7727 |
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.
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