# BCR::ABL1 (Philadelphia chromosome)

Source: https://onco.cc/pathways/bcr-abl1-signalling/  
OnCo record `bcr-abl1-signalling` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Chronic myeloid leukaemia is caused by one broken gene: two chromosomes swap pieces and glue a kinase (ABL1) to a protein that forces it permanently on. Imatinib, the first drug to target it, turned a fatal disease into a manageable one, and later drugs cover the mutations that escape it.

## Summary

The t(9;22) translocation fuses BCR to ABL1, producing a constitutively active cytoplasmic tyrosine kinase (p210 in CML, p190 in most Ph-positive ALL). BCR::ABL1 autophosphorylates and recruits GRB2/GAB2 to activate RAS-MAPK and PI3K-AKT, phosphorylates STAT5 for survival and CRKL for adhesion changes, and raises reactive oxygen species that drive further mutations (blast crisis). Imatinib (2001) binds the inactive kinase conformation; dasatinib, nilotinib and bosutinib are more potent second-generation ATP-site inhibitors; ponatinib covers the T315I gatekeeper mutation; asciminib (2021) binds the myristoyl pocket (STAMP) and works with ATP-site drugs against compound mutations. Response is tracked by BCR::ABL1 transcript levels (major molecular response, MR4.5), and about half of patients with sustained deep response can stop treatment in treatment-free remission. Ph-positive ALL is treated with TKIs plus chemotherapy or blinatumomab.

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: A car accelerator pedal welded to the floor (BCR::ABL1). Imatinib wedges a block under the pedal so it cannot be pressed; some engines change the pedal's shape (T315I) so the block no longer fits, and ponatinib or asciminib are blocks cut for the new shape.
- Interventions: Imatinib, the first-generation ATP-site inhibitor; dasatinib, nilotinib, bosutinib as more potent second-generation options; Ponatinib for the T315I gatekeeper mutation; Asciminib, an allosteric STAMP inhibitor, alone or with an ATP-site inhibitor against compound mutations; Molecular monitoring (BCR::ABL1 transcripts) to guide treatment-free remission attempts; In Ph-positive ALL: TKI with chemotherapy or with blinatumomab, and transplant for high-risk disease

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Philadelphia_chromosome
- Wikipedia: https://en.wikipedia.org/wiki/Philadelphia_chromosome

## Connected records

- cancers: [Acute lymphoblastic leukaemia](https://onco.cc/cancers/all-leukemia/), [Chronic myeloid leukaemia (CML)](https://onco.cc/cancers/cml/), [Chronic myeloid leukaemia, accelerated and blast phase](https://onco.cc/cancers/cml-advanced-phase/), [Chronic myeloid leukaemia, chronic phase](https://onco.cc/cancers/cml-chronic-phase/), [Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)](https://onco.cc/cancers/all-paediatric-ph-positive/)
- targets: [ABL1](https://onco.cc/targets/abl1/), [BCR::ABL1 (Philadelphia chromosome)](https://onco.cc/targets/bcr-abl/), [GAB2](https://onco.cc/targets/gab2/), [GRB2](https://onco.cc/targets/grb2/), [KRAS](https://onco.cc/targets/kras/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [STAT5 (STAT5A, STAT5B)](https://onco.cc/targets/stat5/)
- drugs: [Asciminib](https://onco.cc/drugs/asciminib/), [Bosutinib](https://onco.cc/drugs/bosutinib/), [Dasatinib](https://onco.cc/drugs/dasatinib/), [Imatinib](https://onco.cc/drugs/imatinib/), [Nilotinib](https://onco.cc/drugs/nilotinib/), [Ponatinib](https://onco.cc/drugs/ponatinib/)
- pathways: [Chronic myeloid leukaemia (KEGG map)](https://onco.cc/pathways/cml-signalling/), [JAK-STAT signalling](https://onco.cc/pathways/jak-stat/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)

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