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The genetic basis of early T-cell precursor acute lymphoblastic leukaemia
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Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL. This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia. The early T-cell precursor (ETP) subtype of childhood acute lymphoblastic leukaemia (ALL) has a poor prognosis when treated with standard chemotherapy. Whole genome sequencing is used here to gain insights into the genetic basis of the condition. The results reveal a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, lesions that disrupt haemopoiesis (many of which arise from chromosomal rearrangements that generate novel chimeric in-frame fusion genes), and inactivating mutations in histone modifying genes. This mutation pattern resembles that of myeloid malignancies, suggesting that myeloid-directed therapies such as high-dose cytarabine, or targeted therapies that inhibit cytokine receptor and JAK signalling, might be effective in ETP ALL.
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“High frequency of mutations in EZH2, EED, and SUZ12 are observed in patients with early T cell precursor ALL (ETP-ALL) [154, 155].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [155]
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“Analyses of human leukaemia cases 2,24–26 have shown that JMJD3 is morehighlyexpressedinT-ALLcellsthaninnormalT-cellprogenitors 24 or in other types of leukaemia 25,26 , which is similar to the expression of theclassicNOTCH1target HES1 (Fig.1e).”
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BackgroundResultInfluentialChromatin repressive complexes in stem cells, development, and cancer
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Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
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Self-citationThe Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability
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GenVisR: Genomic Visualizations in R
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BackgroundA 50-Year Journey to Cure Childhood Acute Lymphoblastic Leukemia
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BackgroundSelf-citationT-cell acute lymphoblastic leukemia
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Self-citationSomatic mutations of SUZ12 in malignant peripheral nerve sheath tumors
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“Recently, constitutively active IL-7 receptors have been reported to transmit IL-7 signaling without the need for ligand or the common receptor gamma chain (γc), as a result of IL-7Rα homodimerization due to cysteine and/or proline insertions in the transmembrane domain (13,14).”
Background
Metadata
- Authors
- Zhang, J., Ding, L., Holmfeldt, L., Wu, G., Heatley, S. L., Payne-Turner, D., Easton, J., Chen, X., Wang, J., Rusch, M., Lu, C., Chen, S.-C., Wei, L., Collins-Underwood, J. R., Ma, J., Roberts, K. G., Pounds, S. B., Ulyanov, A., Becksfort, J., Gupta, P., Huether, R., Kriwacki, R. W., Parker, M., McGoldrick, D. J., Zhao, D., Alford, D., Espy, S., Bobba, K. C., Song, G., Pei, D., Cheng, C., Roberts, S., Barbato, M. I., Campana, D., Coustan-Smith, E., Shurtleff, S. A., Raimondi, S. C., Kleppe, M., Cools, J., Shimano, K. A., Hermiston, M. L., Doulatov, S., Eppert, K., Laurenti, E., Notta, F., Dick, J. E., Basso, G., Hunger, S. P., Loh, M. L., Devidas, M., Wood, B., Winter, S., Dunsmore, K. P., Fulton, R. S., Fulton, L. L., Hong, X., Harris, C. C., Dooling, D. J., Ochoa, K., Johnson, K. J., Obenauer, J. C., Evans, W. E., Pui, C.-H., Naeve, C. W., Ley, T. J., Mardis, E. R., Wilson, R. K., Downing, J. R., & Mullighan, C. G.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Washington University in St. Louis (US)
- KU Leuven (BE)
- University of California, San Francisco (US)
- University Health Network (CA)
- University of Padua (IT)
- Children's Hospital Colorado (US)
- University of Florida Health (US)
- Seattle Children's Hospital (US)
- University of New Mexico (US)
- Corresponding author
- Downing, James R.
- Mullighan, Charles G.
- ORCID
- Zhang, Jinghui
- Ding, Li
- Holmfeldt, Linda
- Wu, Gang
- Payne-Turner, Debbie
- Easton, John
- Chen, Xiang
- Wang, Jianmin
- Rusch, Michael
- Lu, Charles
- Chen, Shann-Ching
- Wei, Lei
- Ma, Jing
- Roberts, Kathryn G.
- Pounds, Stanley B.
- Ulyanov, Anatoly
- Becksfort, Jared
- Gupta, Pankaj
- Huether, Robert
- Kriwacki, Richard W.
- Parker, Matthew
- Zhao, David
- Espy, Stephen
- Song, Guangchun
- Cheng, Cheng
- Barbato, Michael I.
- Campana, Dario
- Raimondi, Susana C.
- Cools, Jan
- Shimano, Kristin A.
- Hermiston, Michelle L.
- Doulatov, Sergei
- Eppert, Kolja
- Laurenti, Elisa
- Notta, Faiyaz
- Dick, John E.
- Basso, Giuseppe
- Hunger, Stephen P.
- Loh, Mignon L.
- Devidas, Meenakshi
- Wood, Brent
- Winter, Stuart
- Fulton, Robert S.
- Fulton, Lucinda L.
- Johnson, Kimberly J.
- Obenauer, John C.
- Evans, William E.
- Pui, Ching-Hon
- Ley, Timothy J.
- Mardis, Elaine R.
- Wilson, Richard K.
- Downing, James R.
- Mullighan, Charles G.
- Venue
- Nature
- Published
- 2012-01
- Volume
- 481
- Issue
- 7380
- Pages
- 157-163
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3267575
- OpenAlex
- W2060605982
- Cited by
- 1,596
- References
- 45
- Citations by year
- 2026: 28 · 2025: 61 · 2024: 85 · 2023: 72 · 2022: 98 · 2021: 131 · 2020: 106 · 2019: 123 · 2018: 100 · 2017: 119 · 2016: 138 · 2015: 122 · 2014: 156 · 2013: 162 · 2012: 90
- FWCI
- 164.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-sa)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Washington University in St. Louis
- American Lebanese Syrian Associated Charities (CA021765)
- Alvin J. Siteman Cancer Center
- Children’s Oncology Group
- National Institutes of Health (CA 021765, CA98543)
- National Human Genome Research Institute (U54HG003079, HG003079, NHGRI U54 HG003079)
- National Cancer Institute (CA114766, CA‐98413, U10CA098413, U24CA114766, CA021765, U10CA098543, CA-98543, R25CA023944, T32CA128583, P30CA021765)
- National Institute of General Medical Sciences (U01GM92666, U01GM092666)
- Topics
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- somatic mutations, Ras signaling, cytokine receptor signalling, chromosomal rearrangements, mutation spectrum, high-dose cytarabine, gene expression profiling, hematopoietic stem cells, pediatric leukemia
- MeSH terms
- Reelin Protein, Child, Hematopoiesis, Histones, Humans, Molecular Sequence Data, Mutation, Genes, ras, Stem Cells, T-Lymphocytes, Translocation, Genetic, Signal Transduction, Leukemia, Myeloid, Acute, Genome, Human, Sequence Analysis, DNA, Age of Onset, Genetic Predisposition to Disease, Receptors, Interleukin-7, Genomics, Janus Kinases, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, DNA Copy Number Variations
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