Elucidation of mechanism of disease resistance and persistence in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by the BCR-ABL receptor tyrosine kinase. Imatinib mesylate (IM) is an inhibitor of BCR-ABL and has been approved for the treatment of CML. IM is well tolerated and highly efficacious as it induces stable long-t...
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|Chronic myeloid leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by the BCR-ABL receptor tyrosine kinase. Imatinib mesylate (IM) is an inhibitor of BCR-ABL and has been approved for the treatment of CML. IM is well tolerated and highly efficacious as it induces stable long-term remissions in the vast majority of patients. Despite its efficacy, a still unresolved issue associated with IM therapy is IM resistance in progressed phases of CML and long-term disease persistence. It has been shown that BCR-ABL mRNA and BCR-ABL-positive progenitor and stem cells remain detectable after years of therapy. Based on the BCR-ABL expression analysis and short term IM exposure experiments of IM-naïve, first diagnosis CML precursor cells it has been suggested that BCR-ABL over-expression contributes to a major extend to the incapability of IM to kill and eradicate primitive precursors and CML stem cells. Interestingly, the BCR-ABL expression level in actual persisting CML precursor clones, and the impact of long term IM therapy on the eradication of CML precursors from different bone marrow compartments was never been thoroughly investigated.
Here we studied a putative novel IM persistence mechanism by directly investigating in residual BCR-ABL-positive progenitor and stem cell clones in chronic phase CML patients in major molecular remission (MMR) under IM. We could first show that IM not only eliminates BCR-ABL positive cells from both primitive (stem cell containing) and more mature bone marrow precursor compartments but also that, in contrast to the currently proposed model, persisting primitive and mature BCR-ABL positive colony forming clones (CFU) expressed significantly less BCR-ABL than CML CFU isolated from initial diagnosis patients. Indeed, lower BCR-ABL expression reduces IM sensitivity of primary bone marrow progenitors engineered to express BCR-ABL. Whereas high BCR-ABL expression level increased IM responsiveness but also the frequency of BCR-ABL kinase mutation development as the most important IM resistance mechanism. This would explain the low propensity of secondary IM resistance in patients, which do achieve a good molecular remission with IM.
Another regulator of BCR-ABL kinase point mutation development has been identified with ICSBP, an interferon regulated gene that was previously found by our group to be downregulated in CML. Lack of ICSBP expression in murine myeloid 32D-BA cells conferred BCR-ABL independent IM resistance and limits the development kinase point mutations. Together, here we described two novel and clinically relevant mechanisms of CML persistence and resistance under IM, which may provide a novel perspective for reassessing treatment strategies aiming at eradicating residual disease in CML and to overcome IM resistance.