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

Abstract

BackgroundChronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is linked to the Philadelphia chromosome presence that generates the BCR–ABL1 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.MethodsHere 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.ResultsIn 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.ConclusionOur 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.

The lysine‐specific methyltransferase KMT 2C/ MLL 3 regulates DNA repair components in cancer

“…These data indicate that KMT2C downregulation is a rather common event in tumorigenesis in several human epithelial tissues. On the other hand, a recent report and our own meta‐analysis of non‐epithelial cancers with the use of the GEPIA web server indicated that, in comparison with respective healthy tissue, KMT2C is expressed at higher levels in glioblastoma multiforme (GBM), brain lower grade glioma (LGG), diffuse large B‐cell lymphomas (DLBL), acute myeloid leukemia (AML), and sarcomas (SARC; Appendix Fig S1). This is in agreement with the fact that KMT2C truncating mutations account for only 0.6% in these cancer types (2/397, 2/512, 0/41, 3/200, and 2/254 cases, respectively; not shown).…”

Immunogenomic Landscape Contributes to Hyperprogressive Disease after Anti-PD-1 Immunotherapy for Cancer

“…Figure S3 showed that the mutated KMT2C , TSC2 , VHL , and CYP2D6 genes were involved in the gene-gene interaction network leading to suppression of the TP53 pathway activity. Previous studies showed that KMT2C (MLL3) co-activates TP53 , whereas KMT2C levels decrease during cancer progression, which correlates with distinct clinical stages ( Ford and Dingwall, 2015 , Lee et al., 2009 , Rabello et al., 2018 ). These results are consistent with our observations in HPD tumors after anti-PD-1 treatment.…”

From Anti-EBV Immune Responses to the EBV Diseasome via Cross-reactivity

“… 77 78 KMT2D alterations are involved in follicular lymphoma and diffuse large B-cell lymphoma, 92 cutaneous T-cell lymphoma and Sézary syndrome, 93 ocular adnexal MALT-type marginal zone lymphomas, 79 and chronic myeloid leukemia. 94 Moreover, KMT2D alterations are involved in intraocular medulloepithelioma, 95 small cell lung cancer, 96 bladder cancer, 97 98 and non-small-cell lung cancer. 99 Of not less importance, alterations of KMT2D have a causal role in Kabuki syndrome 100 that is characterized by skeletal and visceral abnormalities and cardiac anomalies, 101 hyperinsulinism, 102 epilepsy, 103 desmoid fibromatosis, 104 immunopathological manifestations, 105 lupus, 106 and oriental alterations, 107 among others.…”