BCL7A implications in acute myeloid leukemia

Abstract

Cancer is a critical global health issue of our time. It encompasses a wide variety of diseases characterized by uncontrolled cell growth, often resulting from genetic mutations and epigenetic alterations. In recent decades, cancer research has led to the discovery of new biomarkers that improve both diagnosis and patient prognosis, and has paved the way for innovative targeted therapies. Despite these promising results, cancer remains as one of the leading causes of death worldwide. Therefore, further research into the molecular basis of cancer initiation and progression is still of paramount importance. Hematologic malignancies are among the most common forms of cancer. Within hematologic malignancies, acute myeloid leukemia (AML) is the second most common form of leukemia. Although cytogenetic aberrations and genetic mutations are involved in the development and progression of AML, this disease is also conditioned by aberrations in epigenetic mechanisms. Chromatin remodeling is one of the major epigenetic mechanisms. The mammalian switch/sucrose-non-fermenting (mSWI/SNF) complex family is one of the major chromatin remodeling families whose alterations have been found to be highly associated with cancer. B-Cell CLL/lymphoma 7 protein family member A (BCL7A) is a mSWI/SNF subunit which has been observed to be clearly related to hematologic disorders. In fact, in a previous research project carried out in our laboratory, BCL7A was found to be recurrently mutated in diffuse large B-Cell lymphoma (DLBCL) patients’ samples and cell lines. The experimental approaches performed along this project showed that BCL7A plays a tumor suppressor role in DLBCL models. AML has been observed to be related to epigenetic disorders (including chromatin modifiers), and BCL7A has been strongly associated with hematologic disorders in previous studies. Therefore, we hypothesized that BCL7A may even play a role in this type of leukemia. Indeed, in a preliminary analysis of data from AML patients, we found that the BCL7A methylation level was inversely correlated with the BCL7A expression level. This downregulation by DNA methylation is a common tumor suppressor inactivation mechanism that is naturally selected by tumor cells. Furthermore, we performed phenotypic assays using AML cell models in which BCL7A was silenced by genomic DNA methylation. These assays suggest that BCL7A plays a tumor suppressor role in AML models both in vitro and in vivo. We also generated a Bcl7a conditional knock-out (KO) mouse model to study the putative effects of Bcl7a in hematologic cells and tissues in vivo. Nevertheles, Bcl7a ablation did not result in any phenotypic changes. On the other hand, using a clustered regularly interspaced short palindromic repeats (CRISPR) based molecular tool, we performed a targeted demethylation of the BCL7A locus in one of our human cell models to evaluate its phenotype after the expected restoration of BCL7A expression. The slight BCL7A expression restoration yielded at messenger ribonucleic acid (mRNA) and protein levels might be the explanation for the absence of any phenotypic change in cell growth capability. The results obtained in this PhD thesis suggest that BCL7A plays a tumor suppressor role in AML. However, further research is necessary to provide more information to determine whether or not BCL7A is an AML useful biomarker in the diagnosis, classification and prognosis of AML patients. Ultimately, this research might yield valuable knowledge for the development of novel therapies to provide more promising outcomes for AML patients.