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Background  Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is linked to the Philadelphia chromosome presence that generates the  BCR – ABL 1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR–ABL tyrosine kinase. The disease shows three distinct clinical-laboratory stages: chronic phase, accelerated phase and blast crisis. Although patients in the chronic phase respond well to treatment, patients in the accelerated phase or blast crisis usually show therapy resistance and CML relapse. It is crucial, therefore, to identify biomarkers to predict CML genetic evolution and resistance to TKI therapy, considering not only the effects of genetic aberrations but also the role of epigenetic alterations during the disease. Although dysregulations in epigenetic modulators such as histone methyltrasnferases have already been described for some hematologic malignancies, to date very limited data is available for CML, especially when considering the lysine methyltransferase  MLL2/KMT2D  and  MLL3/KMT2C .    Methods  Here we investigated the expression profile of both genes in CML patients in different stages of the disease, in patients showing different responses to therapy with IM and in non-neoplastic control samples. Imatinib sensitive and resistant CML cell lines were also used to investigate whether treatment with other tyrosine kinase inhibitors interfered in their expression.    Results  In patients, both methyltransferases were either upregulated or with basal expression level during the chronic phase compared to controls. Interestingly,  MLL3/KMT2C  and specially  MLL2/KMT2D  levels decreased during disease progression correlating with distinct clinical stages. Furthermore,  MLL2/KMT2D  was decreased in patients resistant to IM treatment. A rescue in the expression of both  MLL  genes was observed in KCL22S, a CML cell line sensitive to IM, after treatment with dasatinib or nilotinib which was associated with a higher rate of apoptosis, an enhanced expression of  p21  ( CDKN1A ) and a concomitant decrease in the expression of  CDK2 ,  CDK4  and  Cyclin B1 (CCNB1)  in comparison to untreated KCL22S control or IM resistant KCL22R cell line, which suggests involvement of p53 regulated pathway.    Conclusion  Our results established a new association between  MLL2/KMT2D  and  MLL3/KMT2C  genes with CML and suggest that  MLL2/KMT2D  is associated with disease evolution and may be a potential marker to predict the development of therapy resistance.

MLL2/KMT2D and MLL3/KMT2C expression correlates with disease progression and response to imatinib mesylate in chronic myeloid leukemia