The genetic basis of early T-cell precursor acute lymphoblastic leukaemia
Open accessAbstract
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 ETP-ALL.
“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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Self-citationThe JAK-STAT pathway at 30: Much learned, much more to do
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The Histone Mark H3K36me3 Regulates Human DNA Mismatch Repair through Its Interaction with MutSα
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BackgroundSelf-citationGenetic Basis of Acute Lymphoblastic Leukemia
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BackgroundDNMT3A in haematological malignancies
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Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia
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Self-citationRole of RUNX1 in hematological malignancies
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“A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells.”
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Mutational signatures: the patterns of somatic mutations hidden in cancer genomes
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“ETV6 mutations encoding truncated proteins with dominant-negative activity are frequently found in early immature T-ALLs (32, 33).”
InfluentialHistone lysine methyltransferases in biology and disease
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Association of Age at Diagnosis and Genetic Mutations in Patients With Neuroblastoma
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BackgroundInfluentialThe mutational landscape of adenoid cystic carcinoma
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“Previous work has implicated MYB as an ACC fusion oncogene with NFIB via a t(6;9) translocation40 (Fig.”
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PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies
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The genetics and mechanisms of T cell acute lymphoblastic leukaemia
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Identification of Early Replicating Fragile Sites that Contribute to Genome Instability
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Chromatin proteins and modifications as drug targets
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Self-citationGenome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia
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“Previous efforts by our group and others have aimed at dissecting additional genetic (De Keersmaecker et al., 2013; Ntziachristos et al., 2012; Zhang et al., 2012) and molecular (Ferrando et al., 2002; Look, 2004) changes that contribute to induction of T-ALL.”
Methionine is a metabolic dependency of tumor-initiating cells
Wang, Z., Yip, L. Y., Lee, J. H. J., Wu, Z., Chew, H. Y., Chong, P. K. W., Teo, C. C., Ang, H. Y.-K., Peh, K. L. E., Yuan, J. X., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0423-5 · Cited by 425 · see citing works
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“WGS and WES mapping, coverage and quality assessment, single nucleotide variation (SNV) and insertion/deletion (indel) detection, tier annotation for sequence mutations, prediction of the deleterious effects of missense mutations, structural variant (SV) detection, and identification of loss of heterozygosity (LOH) ha…”
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Exploring genomic alteration in pediatric cancer using ProteinPaint
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Self-citationThe roles of Polycomb repressive complexes in mammalian development and cancer
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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
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Self-citationThe Pediatric Cancer Genome Project
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Self-citation“Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway
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“S703I Inflammatory Adenoma and Leukemia (50)”
Flip the coin: IL-7 and IL-7R in health and disease
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Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor
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Self-citationThe genetic basis and cell of origin of mixed phenotype acute leukaemia
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Self-citationGermline ETV6 mutations in familial thrombocytopenia and hematologic malignancy
Zhang, M. Y., Churpek, J. E., Keel, S., Walsh, T., Lee, M. K., Loeb, K. R., Gülsüner, S., Pritchard, C. C., Sánchez-Bonilla, M., Delrow, J. J., et al. (2015) · Nature Genetics · doi:10.1038/ng.3177 · Cited by 368 · see citing works
“Arg369Gln III-9 Thrombocytopenia Skin cancer (34) Esophageal stricture, GERD B p.”
Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia
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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).”
Self-citationEnd-joining, translocations and cancer
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“and 14, t(8;14), which is seen in 85% of cases of Burkitt’s lymphoma.”
Hakimi, A. A., Ostrovnaya, I., Reva, B. A., Schultz, N. D., Chen, Y., Gönen, M., Liu, H., Takeda, S., Voss, M. H., Tickoo, S. K., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3886 · Cited by 358 · see citing works
“PBRM1 in pancreatic cancer (14), BAP1 in uveal melanoma andmesothelioma (15, 16), andSETD2 in breast cancer and leukemia (17, 18).”
The genetics and molecular biology of T-ALL
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Self-citationThe Implications of Clonal Genome Evolution for Cancer Medicine
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“Overall, 17% (19/111) of the study population had ETP-ALL/LBL.”
BackgroundResultInfluentialChromatin repressive complexes in stem cells, development, and cancer
Laugesen, A., & Helin, K. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.05.006 · Cited by 352 · see citing works
Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
Tzoneva, G., Pérez-García, A., Carpenter, Z., Khiabanian, H., Tosello, V., Allegretta, M., Paietta, E. M., Racevskis, J., Rowe, J. M., Tallman, M. S., et al. (2013) · Nature Medicine · doi:10.1038/nm.3078 · Cited by 350 · see citing works
Self-citationThe Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability
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“It remains to be seen whether BET inhibition will be as efficient for the treatment of either relapsed T-ALL or highly aggressive T-ALL subtypes, including early T cell progenitor T-ALL, which is also resistant to Notch pathway inhibition (Zhang et al., 2012).”
BackgroundResultInfluentialDevelopmental gene networks: a triathlon on the course to T cell identity
Yui, M. A., & Rothenberg, E. V. (2014) · Nature Reviews Immunology · doi:10.1038/nri3702 · Cited by 342 · see citing works
GenVisR: Genomic Visualizations in R
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“Given a gene of interest, it is often useful to view variant occurrences in the context of the translated protein product (Zhang et al. , 2012).”
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A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia
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“Mouse monoclonal antibodies to β-actin (sc-1615) were purchased from Santa Cruz Biotechnology and to SF2 were purchased from Zymed (32-4500) and were used at a 1:1,000 dilution.”
MethodSelf-citationXie, H., Xu, J., Hsu, J. H.-R., Nguyen, M., Fujiwara, Y., Peng, C., & Orkin, S. H. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.10.001 · Cited by 320 · see citing works
“The roles of PRC2 in hematopoiesis are of particular interest given the recent discoveries of loss-of-function and altered-specificity EZH2 mutants, as well as mutations in EED, SUZ12, and JARID2, in various hematopoietic malignancies (Lohr et al., 2012; McCabe et al., 2012; Morin et al., 2010; Nikoloski et al., 2010;…”
BackgroundA 50-Year Journey to Cure Childhood Acute Lymphoblastic Leukemia
Pui, C.-H., & Evans, W. E. (2013) · Seminars in Hematology · doi:10.1053/j.seminhematol.2013.06.007 · Cited by 368 · see citing works
“The prevalence of mutations in genes regulating RAS signaling, cytokine receptor expression, and chromatin modification suggests that myeloid-directed or epigenetic therapy may improve the clinical outcome for this ALL variant.(25) Traditionally, about 70%–80% of B-ALL cases were classified by modal chromosomal number…”
BackgroundSelf-citationT-cell acute lymphoblastic leukemia
Raetz, E. A., & Teachey, D. T. (2016) · Hematology · doi:10.1182/asheducation-2016.1.580 · Cited by 317 · see citing works
“Notch mutations are more common in mature T-ALLs and are relatively rare in ETP ALL.(44)”
BackgroundInfluentialDeregulation of DUX4 and ERG in acute lymphoblastic leukemia
Zhang, J., McCastlain, K., Yoshihara, H., Xu, B., Chang, Y., Churchman, M. L., Wu, G., Li, Y., Wei, L., Iacobucci, I., et al. (2016) · Nature Genetics · doi:10.1038/ng.3691 · Cited by 309 · see citing works
Self-citationBiology of Childhood 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
- 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 › Public Health, Environmental and Occupational Health › 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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