{"id":74,"date":"2026-08-24T13:06:26","date_gmt":"2026-08-24T13:06:26","guid":{"rendered":"https:\/\/biotrivia.com\/blog\/?p=74"},"modified":"2026-08-24T15:30:58","modified_gmt":"2026-08-24T15:30:58","slug":"the-concept-behind-bcrabl1-positive-cml-treatment-strategy-and-tkd-mutation","status":"publish","type":"post","link":"https:\/\/biotrivia.com\/blog\/the-concept-behind-bcrabl1-positive-cml-treatment-strategy-and-tkd-mutation\/","title":{"rendered":"The concept behind\u00a0 BCR::ABL1\u00a0 positive CML treatment strategy and TKD mutation."},"content":{"rendered":"\n

Chronic myeloid leukaemia (CML), a malignant disease derived from a haematopoietic stem cell clone, CML arises from the t(9;22)(q34;q11) balanced reciprocal translocation between chromosome 9 and 22 that forms the Philadelphia chromosome. The translocation event results in the fusion of the Breakpoint Cluster Region<\/em> (BCR<\/em>) gene with the Abelson proto-oncogene 1<\/em> (ABL1<\/em>) gene, generating the BCR::ABL1<\/em>   fusion gene. which produces an abnormal protein with continuously active tyrosine kinase activity. This protein promotes uncontrolled growth and survival of leukemia cells. The Philadelphia chromosome and BCR-ABL1<\/em> are important diagnostic markers of 90 % CML.<\/p>\n\n\n\n

Tyrosine kinase inhibitors (TKIs) such as imatinib have greatly improved CML survival, and most patients can now live nearly normal lifespans. However, some patients develop TKI resistance, experience disease progression, or cannot tolerate treatment side effects. One of the most important causes of TKI resistance is the development of mutations in the BCR-ABL1<\/em> kinase domain. These mutations can change the structure of the BCR-ABL1<\/em> protein and prevent the TKI from binding effectively. Resistance may also occur through mechanisms that do not directly involve BCR-ABL1.<\/em><\/p>\n\n\n\n

TKI resistance is defined based on the European Leukemia Net (ELN) recommendations. Resistance can be divided into primary and secondary categories Primary resistance is characterised by any of the following: No complete haematological response or Ph+ >95% by 3 months, BCR-ABL1<\/em> >10% or Ph+ >35% by 6 months, or BCR-ABL1 >1%, Ph + \u22651% or complete cytogenetic response by 18 months Secondary resistance is defined by the loss of a previously documented haematological, cytogenetic or molecular response.<\/p>\n\n\n\n

Approximately 25\u201330% of patients initially treated with imatinib may develop resistance. For many patients, changing to another TKI based on the specific BCR-ABL1<\/em> mutation can restore treatment response and achieve a major molecular response. However, the T315I mutation is particularly difficult to treat because it strongly interferes with the binding of several TKIs. Therefore, identifying BCR-ABL1<\/em> mutations is important for selecting the most appropriate treatment and managing resistance. The most common mechanism of relapse for CML patients treated with Imatinib is the appearance of point mutations in the  BCR-ABL<\/em> oncogene that confer resistance to this drug. Insights into the emerging problem of resistance should promote the rational development of alternative, synergistic, and potentially curative treatment strategies. <\/p>\n\n\n\n

THE QUESTION IS WHY AND HOW THESE TKD<\/strong> (Tyrosine Kinsase domain)<\/strong> MUTATIONS GET INTO THE PICTURE LATER. <\/strong><\/p>\n\n\n\n

The key point is that TKD mutations do not usually accumulate simply because the TKI \u201ccauses\u201d mutations. The major mechanism is Darwinian selection of pre-existing or newly arising BCR::ABL1    mutant subclones under TKI pressure, followed in some cases by sequential selection of compound mutations.<\/p>\n\n\n\n

Lets dive into the mechanistic model.<\/strong><\/p>\n\n\n\n

1. Why do<\/strong> BCR::ABL1 <\/em><\/strong>  TKD mutations accumulate during TKI treatment?<\/strong><\/h2>\n\n\n\n

5Lets Think of CML as a population of genetically heterogeneous BCR::ABL1<\/em>   -positive cells, rather than a population of identical cells. Before intitiating the treatment, the leukemia may contain 4 different clones of cells.<\/p>\n\n\n\n

Clone A: BCR::ABL1<\/em>    WT
Clone B: BCR::ABL1<\/em>    + low-frequency Y253H
Clone C: BCR::ABL1<\/em>    + low-frequency T315I
Clone D: BCR::ABL1<\/em>    WT but genetically unstable<\/p>\n\n\n\n

Most of the times the minor clones may remain clinically undetectable and When an ATP-competitive Tyrosine Kinase Inhibitor is given: TKI inhibits the sensitive BCR::ABL1<\/em>    cells  leading to death or suppression of  sensitive clones, Now since there were other clones also present, of which some can be resistant clones,. These resistant clones  survive and having no forceful inhibitions, resistant clones keep expanding.<\/p>\n\n\n\n

Therefore, TKI treatment creates a strong selective bottleneck. The mutation that now becomes detectable after TKI  treatment may therefore have pre-existed at low frequency rather than being newly induced by the drug. Experimental and clinical studies support the existence of pre-existing resistant subclones and subsequent selection (PMID: 14676625<\/a>)<\/p>\n\n\n\n

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