{"entity":{"id":"bcr-abl1-signalling","kind":"pathway","name":"BCR::ABL1 (Philadelphia chromosome)","aka":[],"tldr":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Philadelphia_chromosome","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Philadelphia_chromosome"}],"tags":[],"related":[],"cancers":["cml","all-leukemia"],"sections":[],"technologies":[],"targets":["kras","pik3ca","abl1"],"drugs":["imatinib","dasatinib","nilotinib","bosutinib","ponatinib","asciminib"],"companies":[],"institutions":[],"pathways":["ras-mapk","pi3k-akt-mtor","jak-stat"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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.","nodes":[{"id":"t922","label":"t(9;22) translocation","x":50,"y":5},{"id":"bcrabl","label":"BCR::ABL1 kinase (p210 / p190)","x":50,"y":25},{"id":"grb2","label":"GRB2 / GAB2","x":25,"y":45},{"id":"stat5","label":"STAT5","x":75,"y":45},{"id":"ras","label":"RAS → MAPK","x":15,"y":65,"targetId":"kras"},{"id":"pi3k","label":"PI3K → AKT","x":40,"y":65,"targetId":"pik3ca"},{"id":"ros","label":"Reactive oxygen species → new mutations","x":80,"y":65},{"id":"out","label":"Proliferation, survival, genomic instability → CML, Ph+ ALL","x":50,"y":92}],"edges":[{"from":"t922","to":"bcrabl","type":"activates"},{"from":"bcrabl","to":"grb2","type":"activates"},{"from":"bcrabl","to":"stat5","type":"activates"},{"from":"grb2","to":"ras","type":"activates"},{"from":"grb2","to":"pi3k","type":"activates"},{"from":"bcrabl","to":"ros","type":"activates"},{"from":"ras","to":"out","type":"activates"},{"from":"pi3k","to":"out","type":"activates"},{"from":"stat5","to":"out","type":"activates"},{"from":"ros","to":"out","type":"activates"}],"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"]},"route":"/pathways/bcr-abl1-signalling/","neighbours":{"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"cml-advanced-phase","kind":"cancer","name":"Chronic myeloid leukaemia, accelerated and blast phase","route":"/cancers/cml-advanced-phase/"},{"id":"cml-chronic-phase","kind":"cancer","name":"Chronic myeloid leukaemia, chronic phase","route":"/cancers/cml-chronic-phase/"},{"id":"all-paediatric-ph-positive","kind":"cancer","name":"Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)","route":"/cancers/all-paediatric-ph-positive/"}],"target":[{"id":"abl1","kind":"target","name":"ABL1","route":"/targets/abl1/"},{"id":"bcr-abl","kind":"target","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/targets/bcr-abl/"},{"id":"gab2","kind":"target","name":"GAB2","route":"/targets/gab2/"},{"id":"grb2","kind":"target","name":"GRB2","route":"/targets/grb2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"stat5","kind":"target","name":"STAT5 (STAT5A, STAT5B)","route":"/targets/stat5/"}],"drug":[{"id":"asciminib","kind":"drug","name":"Asciminib","route":"/drugs/asciminib/"},{"id":"bosutinib","kind":"drug","name":"Bosutinib","route":"/drugs/bosutinib/"},{"id":"dasatinib","kind":"drug","name":"Dasatinib","route":"/drugs/dasatinib/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"nilotinib","kind":"drug","name":"Nilotinib","route":"/drugs/nilotinib/"},{"id":"ponatinib","kind":"drug","name":"Ponatinib","route":"/drugs/ponatinib/"}],"pathway":[{"id":"cml-signalling","kind":"pathway","name":"Chronic myeloid leukaemia (KEGG map)","route":"/pathways/cml-signalling/"},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}]}}