BCR::ABL1 (Philadelphia chromosome)
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.
Overview
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.
In one picture
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.
Diagram
top- 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
Pages like this
not linked directly; found by shared links- TargetBCR::ABL1 (Philadelphia chromosome)
- Key paperIRIS: imatinib versus interferon plus cytarabine as first treatment for chronic myeloid leukaemia
Shares Nilotinib, Asciminib, Dasatinib, Chronic myeloid leukaemia (CML).
- TermMolecular response (MMR, MR4, treatment-free remission)
- TermPhiladelphia chromosome (Ph+, BCR::ABL1)
- TermPh-positive ALL
- PairingBCR::ABL1 TKI + blinatumomab (chemotherapy-free Ph+ ALL)
Shares Ponatinib, Dasatinib, Acute lymphoblastic leukaemia.
- InstitutionSeoul St. Mary's Hospital
Shares Nilotinib, Imatinib, Acute lymphoblastic leukaemia.
- IdeaTransplant-free Ph-positive ALL for MRD-negative adults
Shares Ponatinib, Dasatinib, Acute lymphoblastic leukaemia.