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KEGG's CML map is built around one fusion protein, BCR-ABL1, a kinase that never switches off and drives RAS, PI3K and STAT5 signalling. Because a single enzyme causes the disease, a single class of pill (imatinib and its successors) controls it in most patients.
The KEGG chronic myeloid leukaemia map (hsa05220) starts with the t(9;22) translocation that forms the Philadelphia chromosome and fuses BCR on chromosome 22 to ABL1 on chromosome 9. The p210 BCR-ABL1 protein has constitutive tyrosine kinase activity and sits in the cytoplasm, where it phosphorylates adaptor proteins (GRB2, GAB2, CRKL, CBL) and switches on three main effector routes: GRB2/SOS to RAS to RAF to MEK to ERK for proliferation, PI3K to AKT to mTOR (with inhibition of BAD and FOXO) for survival, and STAT5 for BCL-XL expression and cytokine-independent growth. Ren, Nat Rev Cancer, 2005 (doi:10.1038/nrc1567) reviews how these signals, plus reduced adhesion to marrow stroma and genomic instability, together explain the expansion of functionally normal myeloid cells in chronic phase. KEGG also draws the secondary lesions that mark progression to accelerated and blast phase: loss of TP53, RB1 and the CDKN2A locus (p16 and p14ARF), and overexpression of EVI1 or the AML1-EVI1 fusion, which disables TGF-beta growth control.
What drugs do about it: the ATP-competitive tyrosine kinase inhibitors imatinib, dasatinib, nilotinib and bosutinib block the BCR-ABL1 kinase and turn a fatal disease into a manageable chronic one, with many patients able to stop treatment after sustained deep molecular response. Ponatinib covers the T315I gatekeeper mutation, and asciminib binds a separate myristoyl pocket (STAMP inhibitor), giving an option when the ATP site has mutated.
BCR-ABL1 is a light switch glued in the on position, feeding power to three circuits (RAS, PI3K, STAT5) that tell blood cells to multiply. Imatinib and its successors are a cover fitted over the switch; asciminib works from the back of the switch plate, so it still fits when the front is damaged.
Shares Bosutinib, Nilotinib, Asciminib, Chronic myeloid leukaemia, chronic phase.
Shares Bosutinib, Nilotinib, Asciminib, Chronic myeloid leukaemia, chronic phase.
Shares ABL1, Bosutinib, STAT5 (STAT5A, STAT5B), Nilotinib.
Shares Nilotinib, Asciminib, Chronic myeloid leukaemia, chronic phase, Dasatinib.
Shares Ponatinib, Asciminib, Chronic myeloid leukaemia, chronic phase, BCR::ABL1 (Philadelphia chromosome).
Shares Ponatinib, Asciminib, Dasatinib, BCR::ABL1 (Philadelphia chromosome).