CML - Not only BCR-ABL1 matters.

BCR-ABL1 is in the center of chronic myeloid leukemia (CML) pathology, diagnosis and treatment, as confirmed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional mechanisms and events, many of which function independently of BCR-ABL1, play important roles, particularly in terms of leukemic stem cell (LSC) persistence, primary and secondary resistance, and disease progression. Promising therapeutic approaches aim to disrupt pathways which mediate LSC survival during successful TKI treatment, in the hope of improving long-term treatment-free-remission and perhaps provide a functional cure for some patients. Over the years through advances in sequencing technology frequent molecular aberrations in addition to BCR-ABL1 have been identified not only in advanced disease but also in chronic phase CML, often affecting epigenetic regulators such as ASXL1, DNMT3A and TET2. Analyses of serial samples have revealed various patterns of clonal evolution with some mutations preceding the BCR-ABL1 acquisition. Such mutations can be considered to be important co-factors in the pathogenesis of CML and could potentially influence therapeutic strategies in the future.