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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.
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.
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.
Shares Bosutinib, Nilotinib, Asciminib, Chronic myeloid leukaemia, chronic phase.
Shares Nilotinib, Asciminib, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase.
Shares Bosutinib, Nilotinib, Asciminib, Chronic myeloid leukaemia, chronic phase.
Shares Ponatinib, Asciminib, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase.
Shares Ponatinib, Asciminib, Dasatinib, Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL).
Shares Ponatinib, Asciminib, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase.