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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 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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“In addition to the above-mentioned heterozygous missense mutations in the SET domain of EZH2 in lymphomas, a spectrum of somatic missense, nonsense, and frameshift mutations have been found throughout the open reading frame of EZH2 in myeloid malignancies [24] and in T-cell acute lymphoblastic leukemia (T-ALL) [25–27].”
BackgroundLessons from next-generation sequencing analysis in hematological malignancies
Braggio, E., Egan, J. B., Fonseca, R., & Stewart, A. K. (2013) · Blood Cancer Journal · doi:10.1038/bcj.2013.26 · Cited by 57
CTCF and BORIS in genome regulation and cancer
Marshall, A. D., Bailey, C. G., & Rasko, J. E. J. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.10.011 · Cited by 57
Reynolds, C., Roderick, J. E., LaBelle, J. L., Bird, G. H., Mathieu, R., Bodaar, K., Colon, D., Pyati, U. J., Stevenson, K. E., Qi, J., et al. (2014) · Leukemia · doi:10.1038/leu.2014.78 · Cited by 58
The Clonal Evolution of Metastatic Osteosarcoma as Shaped by Cisplatin Treatment
Brady, S. W., Ma, X., Bahrami, A., Satas, G., Wu, G., Newman, S., Rusch, M., Putnam, D. K., Mulder, H. L., Yergeau, D. A., et al. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0620 · Cited by 52
“SNV and indel variant identification and clustering WGS reads were aligned to GRCh37-lite with BWA (9) and somatic SNVs/indels were called with Bambino (10) followed by a postprocess which removes paralogous variants and sequencing artifacts caused by poor quality or alignment artifacts (11).”
MethodSelf-citationFacts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia
Bayón-Calderón, F., Toribio, M. L., & González-García, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207685 · Cited by 62
Liu, D., Xiong, H., Ellis, A. E., Northrup, N. C., Dobbin, K. K., Shin, D. M., & Zhao, S. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005277 · Cited by 57
“Importantly, RELN is significantly mutated in human HNSCC [1,4], non-small cell lung cancer of smokers [54], and acute lymphoblastic leukemia [55].”
BackgroundPharmacological targeting of the cancer epigenome
Mabe, N. W., Perry, J. A., Malone, C. F., & Stegmaier, K. (2024) · Nature Cancer · doi:10.1038/s43018-024-00777-2 · Cited by 61
“…of or LOF mutations in EED , EZH2 or SUZ12 have been observed in approximately 25% of T cell acute lymphoblastic leukemias 53 , almost half of early T cell precursor acute lymphoblastic leukemias 54 , some myeloid malignancies 55,56 and the majority of malignant peripheral nerve sheath tumors 57 .”
Site- and allele-specific polycomb dysregulation in T-cell leukaemia
Navarro, J., Touzart, A., Pradel, L. C., Loosveld, M., Koubi, M., Fenouil, R., Noir, S. L., Maqbool, M. A., Morgado, E., Grégoire, C., et al. (2015) · Nature Communications · doi:10.1038/ncomms7094 · Cited by 56
Recent Advances on NOTCH Signaling in T-ALL
Tzoneva, G., & Ferrando, A. A. (2012) · Current topics in microbiology and immunology · doi:10.1007/82_2012_232 · Cited by 56
Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia
Song, C., Pan, X., Ge, Z., Gowda, C. D. R., Ding, Y., Li, H., Li, Z., Yochum, G. S., Müschen, M., Li, Q., et al. (2015) · Leukemia · doi:10.1038/leu.2015.331 · Cited by 54
Waanders, E., Scheijen, B., Jongmans, M. C. J., Venselaar, H., van Reijmersdal, S. V., van Dijk, A. H. A., Pastorczak, A. K., Weren, R. D. A., van der Schoot, C. E., van de Vorst, M., et al. (2016) · Leukemia · doi:10.1038/leu.2016.277 · Cited by 61
Polycomb repressive complexes in hematological malignancies
Iwama, A. (2017) · Blood · doi:10.1182/blood-2017-02-739490 · Cited by 55
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors
Booth, C. A. G., Barkas, N., Neo, W. H., Boukarabila, H., Soilleux, E. J., Giotopoulos, G., Farnoud, N., Giustacchini, A., Ashley, N., Carrelha, J., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.006 · Cited by 57
Wang, H., Song, C., Ding, Y., Pan, X., Ge, Z., Tan, B., Gowda, C. S., Sachdev, M., Muthusami, S., Ouyang, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679332 · Cited by 56
Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2
Kinkel, S., Galeev, R., Flensburg, C., Keniry, A., Breslin, K. A., Gilan, O., Lee, S. C.-W., Liu, J. J., Chen, K., Gearing, L. J., et al. (2015) · Blood · doi:10.1182/blood-2014-10-603969 · Cited by 54
Ma, Y. P., Dobbins, S. E., Sherborne, A. L., Chubb, D., Galbiati, M., Cazzaniga, G., Micalizzi, C., Tearle, R. G., Lloyd, A. L., Hain, R. D., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221099110 · Cited by 54
“The t (9, 18, 12;21) rearrangement did not have the typical configuration of the ETV6/RUNX1 translocation generally documented; chromosome 21 sequence was identified on der(9) but not on der(12) as expected.”
BackgroundLinossi, E. M., Chandrashekaran, I. R., Kolesnik, T. B., Murphy, J. M., Webb, A. I., Willson, T. A., Kedzierski, Ł., Bullock, A. N., Babon, J. J., Norton, R. S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070536 · Cited by 54
“activating mutations associated with acute lymphoblastic leukemia (ALL) [4,5].”
BackgroundOverexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma
Silva, A., Almeida, A. R. M., Cachucho, A., Neto, J. L., Demeyer, S., Matos, M., Hogan, T. V., Li, Y., Meijerink, J. P. P., Cools, J., et al. (2021) · Blood · doi:10.1182/blood.2019000553 · Cited by 54
Self-citationYang, L., Chen, F., Zhu, H.-C., Chen, Y., Dong, B., Shi, M.-L., Wang, W., Jiang, Q., Zhang, L.-P., Huang, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24044-5 · Cited by 44
Degryse, S., de Bock, C. E., Demeyer, S., Govaerts, I., Bornschein, S., Verbeke, D., Jacobs, K., Binos, S., Skerrett-Byrne, D. A., Murray, H. C., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0241-7 · Cited by 54
Self-citationCytogenetic and Molecular Predictors of Outcome in Acute Lymphocytic Leukemia: Recent Developments
Iacobucci, I., Papayannidis, C., Lonetti, A., Ferrari, A., Baccarani, M., & Martinelli, G. (2012) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-012-0122-5 · Cited by 56
Epigenetic Modifications in Pediatric Acute Lymphoblastic Leukemia
Burke, M. J., & Bhatla, T. (2014) · Frontiers in Pediatrics · doi:10.3389/fped.2014.00042 · Cited by 54
“Whole genome sequencing of 12 cases of ETP ALL identified mutations in genes encoding components of the polycomb repressor complex 2 (PRC2), including deletions and sequence mutations of EZH2, SUZ12, and EED (47).”
BackgroundDevelopment of Second-Generation Indole-Based Dynamin GTPase Inhibitors
Gordon, C. P., Venn‐Brown, B., Robertson, M. J., Young, K. A., Chau, N., Mariana, A., Whiting, A., Chircop, M., Robinson, P. J., & McCluskey, A. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300844m · Cited by 53
Gusscott, S., Jenkins, C. E., Lam, S. H. L., Giambra, V., Pollak, M., & Weng, A. P. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161158 · Cited by 53
The biology of Philadelphia chromosome-like ALL
Roberts, K. G. (2017) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2017.07.003 · Cited by 53
Self-citationAbdelali, R. B., Asnafi, V., Petit, A., Micol, J., Callens, C., Villarèse, P., Delabesse, É., Reman, O., Leprêtre, S., Cahn, J.-Y. Y., et al. (2013) · Haematologica · doi:10.3324/haematol.2013.086082 · Cited by 53
“Median age (range) 25 (12-46) 15 (3-45) 0.”
Knoechel, B., Bhatt, A. S., Li, P., Pedamallu, C. S., Severson, E. A., Gutiérrez, A., Dorfman, D. M., Kuo, F. C., Kluk, M., Kung, A. L., et al. (2015) · Molecular Case Studies · doi:10.1101/mcs.a000539 · Cited by 55
Poly‐gene fusion transcripts and chromothripsis in prostate cancer
Wu, C., Wyatt, A. W., McPherson, A., Lin, D., McConeghy, B. J., Mo, F., Shukin, R., Lapuk, A. V., M. Jones, S. J., Zhao, Y., et al. (2012) · Genes, Chromosomes and Cancer · doi:10.1002/gcc.21999 · Cited by 51
“In a separate study into early T-cell precursor acute lymphoblastic leukaemia, Zhang et al. (2012) suggested a link between mutations in DNA repair genes and complex genome rearrangements resembling chromothripsis.”
ResultNext-Generation Evaluation and Treatment of Pediatric Acute Lymphoblastic Leukemia
Heikamp, E., & Pui, C. (2018) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2018.07.039 · Cited by 51
Self-citationMixed Phenotype Acute Leukemia: Current Approaches to Diagnosis and Treatment
Alexander, T., & Orgel, E. (2021) · Current Oncology Reports · doi:10.1007/s11912-020-01010-w · Cited by 52
Raivola, J., Haikarainen, T., Abraham, B. G., & Silvennoinen, O. (2021) · Cancers · doi:10.3390/cancers13040800 · Cited by 54
“Similar to JAK1 and JAK2 mutations, the most prevalent mutations in JAK3: M511I [85], A573V, and R657Q can drive several types of leukemia [52,85,86].”
BackgroundSphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo
Li, Y., Weng, W., Sun, Z., Fu, X., Ma, J., & Zhuang, W.-F. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.03.114 · Cited by 52
Self-citationAnderson, N. M., Harrold, I., Mansour, M. R., Sanda, T., McKeown, M. R., Nagykary, N., Bradner, J. E., Zhang, G. L., Look, A. T., & Feng, H. (2013) · Leukemia · doi:10.1038/leu.2013.377 · Cited by 52
RasGRP Ras guanine nucleotide exchange factors in cancer
Ksionda, O., Limnander, A., & Roose, J. P. (2013) · Frontiers in Biology · doi:10.1007/s11515-013-1276-9 · Cited by 52
Comparison of genome sequencing and clinical genotyping for pharmacogenes
Yang, W., Wu, G., Broeckel, U., Smith, C., Turner, V., Haidar, C. E., Wang, S., Carter, R., Karol, S. E., Neale, G. A. M., et al. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.411 · Cited by 52
Self-citationMultifaceted role of the polycomb-group gene EZH2 in hematological malignancies
Sashida, G., & Iwama, A. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-2124-x · Cited by 55
Mito, J. K., Qian, X., Doyle, L. A., Hornick, J. L., & Jo, V. Y. (2017) · American Journal of Clinical Pathology · doi:10.1093/ajcp/aqx060 · Cited by 52
Patel, A. A., Thomas, J., Rojek, A. E., & Stock, W. (2020) · Current Treatment Options in Oncology · doi:10.1007/s11864-020-00757-5 · Cited by 52
A practical approach to the modern diagnosis and classification of T- and NK-cell lymphomas
de Leval, L., Gaulard, P., & Doǧan, A. (2024) · Blood · doi:10.1182/blood.2023021786 · Cited by 51
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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