Genetic landscape of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the BCR::ABL1 fusion gene, which aberrantly activates ABL1 kinase and promotes the overproduction of leukemic cells. CML typically develops in the chronic phase (CP) and progresses to a blast crisis (BC) after years without effective treatment. Although prognosis has substantially improved after the development of tyrosine kinase inhibitors (TKIs) targeting the BCR::ABL1 oncoprotein, some patients still experience TKI resistance and poor prognosis. One of the mechanisms of TKI resistance is ABL1 kinase domain mutations, which are found in approximately half of the cases, newly acquired during treatment. Moreover, genetic studies have revealed that CML patients carry additional mutations that are also observed in other myeloid neoplasms. ASXL1 mutations are often found in both CP and BC, whereas other mutations, such as those in RUNX1, IKZF1, and TP53, are preferentially found in BC. The presence of additional mutations, such as ASXL1 mutations, is a potential biomarker for predicting therapeutic efficacy. The mechanisms by which these additional mutations affect disease subtypes, drug resistance, and prognosis need to be elucidated. In this review, we have summarized and discussed the landscape and clinical impact of genetic abnormalities in CML.