How can Chronic Myeloid Leukaemic drugs (Tyrosine kinase inhibitors, e.g. imatinib, etc.) that act by inhibiting bind of ATP to the active site of the BCR-ABL1 protein actually reduce the prevalence of the Philadelphia chromosome? (For example, optimal response to TKIs in 3 months would be Ph+ <35% and/or BCR-ABL1 <10%.) What I am actually asking is how a drug that targets the result of the oncogene (the BCR-ABL1 protein) can have an effect on the source (ie. genotype of the cells), as CML is a clonal haematopoietic stem cell disorder?

An example Reference paper: Apperley JF. Chronic myeloid leukaemia. Lancet. 2015 Apr 11;385(9976):1447-59. doi: 10.1016/S0140-6736(13)62120-0. Epub 2014 Dec 5. PMID: 25484026.

  • $\begingroup$ Very interesting question! Could you cite a paper too? thanks $\endgroup$ – Evan P Oct 14 '20 at 11:24
  • $\begingroup$ @EvanP Just added. Thanks! $\endgroup$ – Lina Oct 14 '20 at 11:31

The key is that TKIs, such as Imatinib, are a therapy rather than a cure

Per Wikipedia, Imatinib acts as a competitive inhibitor of the otherwise constitutively-active BCR-ABL fusion protein, rather than the fusion gene. By binding the kinase domain, BCR-ABL is unable to phosphorylate downstream effectors that result in unchecked proliferation. As long as a patient continues to take Imatinib, BCR-ABL activity should be blocked.

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In the past few years (i.e, long after imatinib's discovery) there has been a lot of research into exactly how hematopoetic stem cells, which reside in the marrow and create leukemic blasts, work. Most HSCs remain in a quiescent state, but it's not particularly well-known how frequently they turn over. Recent CML studies have shown that after ~5 years, a large portion of CML patients can safely taper the the drug. Presumably this is related to HSC turnover, but frankly as a leukemia molecular biologist rather than a physician, I'm not the best font of clinical knowledge.


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