# ABL1
**ABL1** (ABL proto-oncogene 1, non-receptor tyrosine kinase; also called c-ABL) is a human protein-coding gene on chromosome 9 at 9q34.12 that encodes a non-receptor tyrosine kinase involved in cell division, adhesion, differentiation, and the response to stress.[1](https://www.ncbi.nlm.nih.gov/gene/000025) The gene first came to light through its viral counterpart, v-abl, the tumor gene of the Abelson murine leukemia virus, and its oncogenic importance in humans rests chiefly on the BCR-ABL1 fusion protein produced by the t(9;22) [Philadelphia chromosome](https://www.edgepedia.org/philadelphia-chromosome) translocation, the driver of chronic myeloid leukemia (CML).[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
| Key fact | Detail |
|---|---|
| Gene | ABL1, HGNC:76, Gene ID 25; protein coding; location 9q34.12 on chromosome 9; 12 exons[1](https://www.ncbi.nlm.nih.gov/gene/000025) |
| Protein | Non-receptor tyrosine kinase with an SH3-SH2-kinase (SH1) cassette, an N-terminal cap, and a C-terminal region carrying F-actin-binding, DNA-binding, and protein-interaction domains[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) |
| Regulation | Activity is negatively regulated by the SH3 domain and by autoinhibitory interactions including myristoyl-group binding to the kinase domain; phosphorylation of Y412 and Y245 enhances catalytic activity[1](https://www.ncbi.nlm.nih.gov/gene/000025) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) |
| Paralog | ABL2 (also called Arg, Abl-related gene), identified by sequence similarity; the two vertebrate paralogs have specialized functions[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) |
| Oncogenic fusion | t(9;22) translocation fuses the 5' end of BCR to ABL1, producing BCR-ABL1, common in chronic myeloid leukemia and found in other leukemias[1](https://www.ncbi.nlm.nih.gov/gene/000025) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) |
| Drug target | Four generations of tyrosine kinase inhibitors target BCR-ABL1; imatinib was the first FDA-approved BCR::ABL1 inhibitor[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC11586107/pdf/nihms-2034759.pdf) • [5](https://www.nature.com/articles/s41551-025-01531-4) |
| Key resistance mutation | T315I, the gatekeeper mutation, is resistant to most ATP-competitive inhibitors; ponatinib and asciminib are recommended for it[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC12310532/) |
## Gene and protein structure
The official symbol ABL1 and the full name ABL proto-oncogene 1, non-receptor tyrosine kinase are provided by HGNC, and the RefSeq record is reviewed.[1](https://www.ncbi.nlm.nih.gov/gene/000025) [Alternative splicing](https://www.edgepedia.org/alternative-splicing) produces two transcript variants that contain alternative first exons spliced to a common set of downstream exons; the 1b isoforms carry an N-terminal glycine that is myristoylated.[1](https://www.ncbi.nlm.nih.gov/gene/000025) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
The protein combines a regulated SH3-SH2-TK (Src homology 3, Src homology 2, tyrosine kinase) domain cassette with cytoskeletal protein-binding and DNA-binding domains, a combination that gives ABL proteins signaling capabilities distinct from most other cytoplasmic kinases.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) The long C-terminal tail, termed the last exon region, carries numerous protein-protein interaction sites, including conserved proline-rich sequences that bind SH3 or WW domains.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3513796/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
## Regulation of kinase activity
**Autoinhibition.** Full-length Abl kinase activity is low in vitro and hard to detect in unstimulated cells, while the isolated kinase domain has a 10- to 100-fold higher activity, showing that the surrounding domains dampen catalysis.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3513796/) Several mechanisms enforce the inactive state: a myristoyl group attached to the N-terminal glycine of the 1b isoform nestles into a surface pocket in the kinase domain; a short N-terminal "Cap" sequence stabilizes the inactive conformation; and the SH3 and SH2 domains cradle the kinase domain, forming an SH3-SH2-SH1 clamp.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) The crystal structure of regulated Abl resembles that of regulated Src-family kinases, with the distinctive feature that myristate binding to a hydrophobic pocket induces a conformational change enabling the [SH2 domain](https://www.edgepedia.org/sh2-domain) to dock onto the kinase domain.[8](https://www.nature.com/articles/nrm1280) Even a partial but persistent disruption of these autoinhibitory constraints results in oncogenic transformation, and deletion of the region encoding the [SH3 domain](https://www.edgepedia.org/sh3-domain) converts the gene into an oncogene.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3513796/) • [1](https://www.ncbi.nlm.nih.gov/gene/000025)
**Activation.** [Phosphorylation](https://www.edgepedia.org/phosphorylation) of tyrosine 412 in the activation loop of the kinase domain enhances catalytic activity, and phosphorylation of tyrosine 245 in the SH2-kinase linker further enhances activity by disrupting inhibitory intramolecular interactions.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) Abl kinases are activated by diverse stimuli, including growth factors, chemokines, DNA damage, oxidative stress, adhesion receptors, and microbial pathogens.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) Rather than acting as a simple on-off switch, Abl is better understood as existing in a [dynamic equilibrium](https://www.edgepedia.org/dynamic-equilibrium) of states that can be shifted by phosphorylation, intramolecular interactions, binding partners, and subcellular localization.[9](https://pubmed.ncbi.nlm.nih.gov/11779715/)
## Normal functions
**Cytoskeleton and cell behavior.** The most evolutionarily conserved function of the Abl kinases is regulation of cytoskeletal dynamics. Activated by growth-factor-stimulated receptor tyrosine kinases, they drive actin reorganization needed for lamellipodial protrusions, membrane ruffles, migration, adhesion, and endocytosis, in part through phosphorylation of targets such as cortactin, N-WASP, and WAVE proteins and through the small GTPases Rac1, RhoA, and Rap1.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) The C-terminal F-actin-binding and -bundling domain connects phosphoregulation directly to actin-filament reorganization.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/)
**DNA damage response.** ABL1 carries three nuclear localization signals, a nuclear export signal, and a [DNA-binding domain](https://www.edgepedia.org/dna-binding-domain), and shuttles between cytoplasm and nucleus.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) In response to damage signals it associates directly with DNA and interacts with many [DNA repair](https://www.edgepedia.org/dna-repair) mediators, including ATM, ATR, RAD51, and WRN. Overexpression of ABL1 causes cell cycle arrest and apoptosis in cultured cells, suggesting that ABL1 promotes a repair checkpoint after moderate DNA damage but cell death after severe damage; targets such as MDM2, TP53, and TP73 mediate this damage-induced apoptosis.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/) These nuclear features are weak or absent in ABL2 and in invertebrate Abl proteins, indicating that DNA damage-response functions evolved after the ABL gene duplication.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/)
**Physiology revealed by knockout mice.** Abl1-knockout mice are viable or show perinatal lethality depending on strain, and display splenic and thymic atrophy, reduced B- and T-cell numbers, cardiac abnormalities, and osteoporosis linked to defective osteoblast proliferation; Abl2 knockouts instead show neuronal defects. Mice lacking both genes die by embryonic day 11, evidence of functional overlap.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
## BCR-ABL1 and leukemia
In numerous forms of leukemia, this gene can fuse with a range of different translocation partners; the best-known example is the t(9;22) rearrangement, which joins it to the 5' end of the breakpoint cluster region gene (BCR).[1](https://www.ncbi.nlm.nih.gov/gene/000025) The resulting BCR-ABL1 chimeric protein has elevated tyrosine kinase and transforming activity and occurs in Philadelphia chromosome-positive leukemias including chronic myeloid leukemia and acute lymphocytic leukemia.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) The fusion adds the BCR N-terminal coiled-coil domain, severely abrogates ABL1 autoregulation, and changes kinase dynamics, driving phosphorylation of substrates in the GRB2/GAB2, CRKL, JAK/STAT, MAPK, and PI3K/AKT pathways.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10970269/) Oncogenic forms of both ABL1 and ABL2 also occur in some [T-cell acute lymphoblastic leukemia](https://www.edgepedia.org/t-cell-acute-lymphoblastic-leukemia) and acute myeloid leukemia through ETV6 translocations.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
## Targeting ABL1 kinases and resistance
**Inhibitor classes.** ATP-competitive inhibitors of the Abl kinases divide into type I inhibitors that bind the active kinase conformation (dasatinib, bosutinib) and type II inhibitors that bind the inactive conformation (imatinib, nilotinib, ponatinib). A third class, allosteric inhibitors such as GNF2 and GNF5, binds the myristoyl-binding pocket in the C-lobe instead of the ATP site and is highly selective for the Abl kinases.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/) Imatinib was the first FDA-approved BCR::ABL1 inhibitor; during its clinical use, resistance arose through secondary point mutations at at least 25 residues in the BCR::ABL1 kinase domain.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC11586107/pdf/nihms-2034759.pdf)
**Clinical impact.** CML was once considered incurable, with a median survival of 3 to 6 years; BCR::ABL1 tyrosine kinase inhibitors have largely normalized life expectancy for most patients in the chronic phase.[11](https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35832) Resistance remains a major clinical challenge, driven by ABL1 kinase-domain mutations and by quiescent leukemia stem cells in the bone marrow.[12](https://www.mdpi.com/1422-0067/25/6/3307/pdf?version=1710425729)
**Mutation-guided drug choice.** BCR::ABL1 mutations are at present the only actionable mechanism of resistance, and mutation testing is indicated when resistance or progression is suspected; detecting a specific mutant helps exclude inhibitors unlikely to be effective.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC12310532/) The T315I gatekeeper mutation responds to ponatinib and asciminib, while mutations lining the myristoyl-binding pocket (for example A337V/T, L340Q, and V506L/M) specifically confer resistance to asciminib but leave ATP-competitive inhibitors effective.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC12310532/) Asciminib, the first regulatory-site inhibitor approved for a hematological malignancy, achieved a major molecular response rate of 25.5 percent at 24 weeks versus 13.2 percent for bosutinib in heavily pretreated CML in the ASCEMBL trial.[13](https://www.sciencedirect.com/science/article/abs/pii/S0006295226007756) The third-generation inhibitor [olverembatinib](https://www.edgepedia.org/olverembatinib) is approved in China for TKI-resistant chronic-phase and accelerated-phase CML, including disease with the T135I mutation.[11](https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35832) A 2025 prime-editing study built a comprehensive resistance map of CML-associated ABL1 variants against five tyrosine kinase inhibitors to complement clinical guidelines in drug selection.[5](https://www.nature.com/articles/s41551-025-01531-4)
**Beyond leukemia.** Because endogenous Abl kinases participate in inflammation-linked pathologies and are subverted by microbial pathogens (Abl kinase activity is required for internalization of [Shigella flexneri](https://www.edgepedia.org/shigella-flexneri) and for HIV-1 entry into host cells), Abl inhibitors developed for CML are being considered for other conditions with hyperactive Abl signaling.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
## References
1. [ABL1 ABL proto-oncogene 1, non-receptor tyrosine kinase [Homo sapiens], NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/000025)
2. [ABL Tyrosine Kinases: Evolution of Function, Regulation, and Specificity, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2954126/)
3. [Khatri, Wang, Pendergast (2016). Multifunctional Abl kinases in health and disease, Journal of Cell Science, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4732293/)
4. [Overcoming Secondary Mutations of Type II Kinase Inhibitors, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11586107/pdf/nihms-2034759.pdf)
5. [Comprehensive resistance profiling of chronic myeloid leukaemia associated ABL1 variants against five tyrosine kinase inhibitors using prime editing, Nature Biomedical Engineering (2025)](https://www.nature.com/articles/s41551-025-01531-4)
6. [2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12310532/)
7. [Structure, Regulation, Signaling, and Targeting of Abl Kinases in Cancer, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3513796/)
8. [Hantschel & Superti-Furga (2004). Regulation of the c-Abl and Bcr-Abl tyrosine kinases, Nature Reviews Molecular Cell Biology](https://www.nature.com/articles/nrm1280)
9. [Smith & Mayer (2002). Abl: mechanisms of regulation and activation, PubMed](https://pubmed.ncbi.nlm.nih.gov/11779715/)
10. [Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10970269/)
11. [Kantarjian et al. (2025). Olverembatinib in chronic myeloid leukemia, Cancer](https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35832)
12. [Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia, IJMS (MDPI)](https://www.mdpi.com/1422-0067/25/6/3307/pdf?version=1710425729)
13. [Allosteric kinase inhibition in hematological malignancies: from asciminib to emerging regulatory sites, Biochemical Pharmacology](https://www.sciencedirect.com/science/article/abs/pii/S0006295226007756)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Protein families and complexes › Kinase and phosphatase families › Protein kinase families › Protein tyrosine kinases › Abl, Ack, and cytoskeleton-associated tyrosine kinases*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 11, 2026; Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license