How can Chronic myeloid Leukaemic drugs reduce the production of the Philadelphia genotype?

Question

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.

Answer 1

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.

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.