BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros
Abstract
The Philadelphia chromosome, a chromosomal abnormality that encodes BCR-ABL1, is the defining lesion of chronic myelogenous leukaemia (CML) and a subset of acute lymphoblastic leukaemia (ALL). To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed a genome-wide analysis of diagnostic leukaemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CML cases. IKZF1 (encoding the transcription factor Ikaros) was deleted in 83.7% of BCR-ABL1 ALL, but not in chronic-phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG-mediated recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In mice, both Ikzf1 and Ikzf3 are required for normal T cell development and maintenance of mature T cell populations.
“In mice, both Ikzf1 and Ikzf3 are required for normal T cell development and maintenance of mature T cell populations88,89”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [88]
Cites
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia
Mullighan, C. G., Goorha, S., Radtke, I., Miller, C. B., Coustan‐Smith, E., Dalton, J., Girtman, K., Mathew, S., Ma, J., Pounds, S. B., et al. (2007) · Nature · doi:10.1038/nature05690 · Cited by 1,798 · see citing works
Self-citationCharacterizing the cancer genome in lung adenocarcinoma
Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., et al. (2007) · Nature · doi:10.1038/nature06358 · Cited by 1,105 · see citing works
The ikaros gene is required for the development of all lymphoid lineages
Georgopoulos, K., Bigby, M., Wang, J.-H., Molnar, A., Wu, P., Winandy, S., & Sharpe, A. (1994) · Cell · doi:10.1016/0092-8674(94)90407-3 · Cited by 985 · see citing works
Chronic Myeloid Leukemia — Advances in Biology and New Approaches to Treatment
Goldman, J. M., & Melo, J. V. (2003) · New England Journal of Medicine · doi:10.1056/nejmra020777 · Cited by 946 · see citing works
Ehrich, M., Nelson, M. R., Stanssens, P. E., Zabeau, M., Liloglou, T., Xinarianos, G., Cantor, C. R., Field, J. K., & van den Boom, D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507816102 · Cited by 812 · see citing works
Melo, J. (1996) · Blood · doi:10.1182/blood.v88.7.2375.bloodjournal8872375 · Cited by 739 · see citing works
The RAG Proteins and V(D)J Recombination: Complexes, Ends, and Transposition
Fugmann, S. D., Lee, A. I., Shockett, P. E., Villey, I. J., & Schatz, D. G. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.495 · Cited by 648 · see citing works
Chronic myeloid leukaemia as a model of disease evolution in human cancer
Melo, J. V., & Barnes, D. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2147 · Cited by 616 · see citing works
Wang, J., Nichogiannopoulou, A., Wu, L. J., Sun, L., Sharpe, A. H., Bigby, M. E., & Georgopoulos, K. (1996) · Immunity · doi:10.1016/s1074-7613(00)80269-1 · Cited by 614 · see citing works
A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma
Winandy, S., Wu, P. W., & Georgopoulos, K. (1995) · Cell · doi:10.1016/0092-8674(95)90170-1 · Cited by 527 · see citing works
The Ikaros Gene Encodes a Family of Functionally Diverse Zinc Finger DNA-Binding Proteins
Molnár, A., & Georgopoulos, K. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.12.8292 · Cited by 425 · see citing works
Sun, L., Liu, A., & Georgopoulos, K. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00920.x · Cited by 377 · see citing works
Gleibetaner, B. (2002) · Blood · doi:10.1182/blood.v99.5.1536 · Cited by 344 · see citing works
Hahm, K., Ernst, P., Lo, K., Kim, G. S., Turck, C. W., & Smale, S. T. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.11.7111 · Cited by 224 · see citing works
Sun, L., Heerema, N. A., Crotty, L., Wu, X., Navara, C. S., Vassilev, A. O., Sensel, M. G., Reaman, G. H., & Uckun, F. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.2.680 · Cited by 195 · see citing works
Williams, R. T., Roussel, M. F., & Sherr, C. J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602030103 · Cited by 191 · see citing works
Verkaik, N. S., Esveldt, R. E., van Heemst, D., Brüggenwirth, H. T., Hoeijmakers, J. H. J., Zdzienicka, M. Z., & van Gent, D. C. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200203)32:3 · Cited by 189 · see citing works
Ribeiro, R., Abromowitch, M., Raimondi, S. C., Murphy, S., Behm, F. G., & Williams, D. (1987) · Blood · doi:10.1182/blood.v70.4.948.948 · Cited by 169 · see citing works
Molnár, A., Wu, P., Largespada, D. A., Vortkamp, A., Scherer, S. W., Copeland, N. G., Jenkins, N. A., Bruns, G. A. P., & Georgopoulos, K. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.2.585 · Cited by 168 · see citing works
Klug, C. A., Morrison, S. J., Masek, M., Hahm, K., Smale, S. T., & Weissman, I. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.2.657 · Cited by 168 · see citing works
Ikaros, Aiolos and Helios: Transcription regulators and lymphoid malignancies
Rebollo, A., & Schmitt, C. (2003) · Immunology and Cell Biology · doi:10.1046/j.1440-1711.2003.01159.x · Cited by 141 · see citing works
Expression of Aberrantly Spliced Oncogenic Ikaros Isoforms in Childhood Acute Lymphoblastic Leukemia
Sun, L., Goodman, P. A., Wood, C. M., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.12.3753 · Cited by 118 · see citing works
Blast crisis in a murine model of chronic myelogenous leukemia.
Daley, G. Q., Etten, R. A. V., & Baltimore, D. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.24.11335 · Cited by 116 · see citing works
Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia.
Sun, L., Crotty, M. L., Sensel, M. G., Sather, H. N., Navara, C. S., Nachman, J., Steinherz, P. G., Gaynon, P. S., Seibel, N. L., Mao, C., et al. (1999) · PubMed · Cited by 113 · see citing works
Nakase, K., Ishimaru, F., Avitahl, N., Dansako, H., Matsuo, K., Fujii, K., Sezaki, N., Nakayama, H., Yano, T., Fukuda, S., et al. (2000) · PubMed · Cited by 110 · see citing works
The Leukemia-Lymphoma Cell Line Facts Book
Bennett, J. M. (2002) · Leukemia Research · doi:10.1016/s0145-2126(02)00012-7 · Cited by 84 · see citing works
Manabe, A., Coustan‐Smith, E., KUMAGAI, M., et al. (1994) · Blood · doi:10.1182/blood.v83.7.1731.1731 · Cited by 78 · see citing works
Klein, F., Feldhahn, N., Herzog, S., Sprangers, M., Mooster, J. L., Jumaa, H., & Müschen, M. (2005) · Oncogene · doi:10.1038/sj.onc.1209133 · Cited by 64 · see citing works
Olivero, S., Maroc, C., Beillard, E. J., et al. (2000) · British Journal of Haematology · doi:10.1046/j.1365-2141.2000.02297.x · Cited by 46 · see citing works
Expression of the Ikaros gene family in childhood acute lymphoblastic leukaemia
Takanashi, M., Yagi, T., Imamura, T., et al. (2002) · British Journal of Haematology · doi:10.1046/j.1365-2141.2002.03487.x · Cited by 38 · see citing works
Tonnelle, C., Imbert, M.-C., Sainty, D., et al. (2003) · The Hematology Journal · doi:10.1038/sj.thj.6200235 · Cited by 26 · see citing works
Nishii, K., Kita, K., Miwa, H., et al. (2000) · PubMed · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017 · see citing works
Deletion of <i>IKZF1</i> and Prognosis in Acute Lymphoblastic Leukemia
Mullighan, C. G., Su, X., Zhang, J., Radtke, I., Phillips, L. A. A., Miller, C. B., Ma, J., Liu, W., Cheng, C., Schulman, B. A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808253 · Cited by 1,422 · see citing works
Self-citationReynaud, D., Pietras, E., Barry-Holson, K., Mir, A., Binnewies, M., Jeanne, M., Sala-Torra, O., Radich, J. P., & Passegué, E. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.10.012 · Cited by 335 · see citing works
The prenatal origins of cancer
Marshall, G. M., Carter, D. R., Cheung, B. B., Liu, T., Mateos, M. K., Meyerowitz, J. G., & Weiss, W. A. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3679 · Cited by 281 · see citing works
Molecular genetics of B-precursor acute lymphoblastic leukemia
Mullighan, C. G. (2012) · Journal of Clinical Investigation · doi:10.1172/jci61203 · Cited by 247 · see citing works
Self-citationChromosomal Abnormalities in Cancer
Fröhling, S., & Döhner, H. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0803109 · Cited by 229 · see citing works
Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia
on behalf of the International CML Foundation Genomics Alliance, Branford, S., Kim, D. D. H., Apperley, J. F., Eide, C. A., Mustjoki, S., Ong, S. T., Nteliopoulos, G., Ernst, T., Chuah, C., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0512-y · Cited by 149 · see citing works
Self-citationTranscription factor networks in B-cell differentiation link development to acute lymphoid leukemia
Somasundaram, R., Prasad, M. A. J., Ungerbäck, J., & Sigvardsson, M. (2015) · Blood · doi:10.1182/blood-2014-12-575688 · Cited by 135 · see citing works
Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Jan, M., Sperling, A. S., & Ebert, B. L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00479-z · Cited by 137 · see citing works
Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals
Heizmann, B., Kastner, P., & Chan, S. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20131735 · Cited by 101 · see citing works
Magistroni, V., Mauri, M., D’Aliberti, D., Mezzatesta, C., Crespiatico, I., Nava, M., Fontana, D., Sharma, N., Parker, W., Schreiber, A., et al. (2019) · Haematologica · doi:10.3324/haematol.2017.179937 · Cited by 29 · see citing works
Zhang, T., Wang, Y.-F., Montoya, A., Patrascan, I., Nebioglu, N., Pallikonda, H. A., Georgieva, R., King, J. W. D., Kramer, H. B., Shliaha, P. V., et al. (2025) · Blood · doi:10.1182/blood.2024024787 · Cited by 14 · see citing works
- Authors
- Mullighan, C. G., Miller, C. B., Radtke, I., Phillips, L. A., Dalton, J., Ma, J., White, D., Hughes, T. P., Le Beau, M. M., Pui, C.-H., Relling, M. V., Shurtleff, S. A., & Downing, J. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- South Australia Pathology (AU)
- Corresponding author
- Downing, James R.
- ORCID
- Venue
- Nature
- Published
- 2008-04-13
- Volume
- 453
- Issue
- 7191
- Pages
- 110-114
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2119967034
- Cited by
- 1,072
- References
- 32
- Citations by year
- 2026: 11 · 2025: 26 · 2024: 42 · 2023: 47 · 2022: 32 · 2021: 48 · 2020: 58 · 2019: 48 · 2018: 35 · 2017: 73 · 2016: 68 · 2015: 78 · 2014: 73 · 2013: 75 · 2012: 96
- FWCI
- 85.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- BCR-ABL1, acute lymphoblastic leukemia, Ikaros, IKZF1 deletion, Philadelphia chromosome, chronic myeloid leukemia, lymphoid blast crisis, haploinsufficiency, transcription factors, oncogene cooperation, alternative splicing, leukemogenesis
- MeSH terms
- Adult, Child, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Gene Deletion, Protein Structure, Tertiary, Protein Isoforms, Polymorphism, Single Nucleotide, Ikaros Transcription Factor, Precursor Cell Lymphoblastic Leukemia-Lymphoma
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
