Abstract 3513: Decoding the role of myocyte enhancer factor 2C in chronic myeloid leukemia disease progression
Authors: Chakraborty Soumen 
Published: July 2017

Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disorder of hematopoietic stem cell and is marked by the presence of the Philadelphia chromosome, a reciprocal translocation occurring between the long arm of chromosome 9 and 22 resulting in the formation of a fusion BCR-ABL1+ oncogene which encodes a constitutively active non-receptor tyrosine kinase. Clinically, the disease progresses through three phases: an initial chronic phase, accelerated phase and terminal blast phase, which is marked by increased production of immature myeloid precursor cells. Earlier we have shown that BCR-ABL mediated repression of miR-223 results in the activation of mef2C and ptbp2 in chronic myeloid leukemia. Transcription factor MEF2C, required for cell survival and proliferation, is important for lymphopoiesis, and its ectopic expression in myeloid progenitors antagonizes myelopoiesis. We reported that MEF2C expression increases as the disease progresses from chronic phase to blast phase and by knocking down MEF2C in a CML cell line we showed that it negatively correlates with the CEBPA expression, a granulocytic transcription factor. Imatinib, the drug of choice for CML, abrogates MEF2C expression and reverses CEBPA repression both in the cell line and the primary cells. In the present study we observed that when the cells were treated with anisomycin it degraded MEF2C expression in 16hrs which imatinib can achieve after 24hrs. Investigators have demonstrated that anisomycin acts as a potent signaling agonist, synergizing with growth factors and phorbol esters to superinduce immediate-early genes such as c-fos, fosB, c-jun, JunB, and JunD. However here blocking the MAPK kinases with inhibitors didn't reverse the inhibition suggesting that these pathways may not be involved in the anisomycin mediated MEF2C degradation in CML. Mef2c gene consists of three alternative exons, α1/α2, skipping exon β and 3'splice site γ. In order to characterize the role of mef2c gene in CML, first we investigated the different isoforms of mef2c in CML cell line (KCL22) by amplification of the whole mef2c gene and cloning the same in a TOPO vector. Several clones were checked and sequenced. Two different types of isoforms (α1+ β- γ+ and α1+ β- γ-) were found to coexist in KCL22 cells along with an exclusion of 9 bases (AACACAGGT) from the splice junction of exon 4 and 5, which was not reported earlier. However, K562 cells along with KYO-1 and LAMA-84 showed the presence of 9 bases. Nine base pair deletion was also observed in CML patient samples (both CP and BC). Interestingly sequencing of the mef2C genomic region from the cell lines and the same patient samples showed the presence of 9 bases. The different isoforms were transduced in mouse lineage negative bone marrow cells and also transplanted in mice either alone or in combination with BCR-ABL to study the effect of the isoforms in disease progression, the results of which will be discussed.
Citation Format: Soumen Chakraborty. Decoding the role of myocyte enhancer factor 2C in chronic myeloid leukemia disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3513. doi:10.1158/1538-7445.AM2017-3513