Once hidden in the ‘dark genomic matter’, microRNAs (miRNAs) are emerging as important factors in the pathophysiology of cancer, including leukemias. Upregulation of miRNAs that target tumor suppressors or downregulation of miRNAs that target oncogenes can result in tumorigenesis. Such mechanisms may be relevant in leukemia. Thus, specific miRNA expression profiles have been associated with distinct genetic abnormalities in AML, supporting a mechanistic involvement. However, the identity and functions of miRNAs in the initiation and development of leukemia remain largely unknown. Investigations in our lab are largely focused on a detailed understanding of miRNAs role in leukemogenesis, which needs to be established in order to fully explore their clinical translational potential. Our mechanistic studies will inform novel and exciting therapeutic opportunities in AML.
Role of Oncogenic microRNAs in Myelopoiseis and Myeloid Leukemia
Hematopoiesis, the process by which hematopoietic stem cells (HSC) either self-renew or commit to differentiation into discrete lineages, is tightly regulated by both intrinsic factors (signaling networks and transcription factors) and extrinsic factors (bone marrow microenvironment, cell adhesion molecules and cytokines. In general, cytokines regulate hematopoiesis by triggering one or more signaling cascades, with IL-3, GM-CSF and G-CSF acting as dominant regulators of the growth and differentiation of myeloid progenitors. In myeloid progenitor cells, they signal via a common JAK2-STAT5 pathway. MicroRNAs add another regulatory dimension to hematopoiesis, by selectively targeting signaling molecules, receptors, ligands and transcription factors, thereby influencing functional outcomes related to HSC self-renewal, differentiation, apoptosis and the balance of myeloid vs. lymphoid populations within the hematopoietic progenitor pool.
Role of Tumor Suppressor microRNAs in Myeloid Leukemia
Studies in our lab are also focused on two miroRNAs miR-199b and miR-125a that are significantly silenced in AML. Though we and others have previously demonstrated their respective silencing in AML, their clinical significance, mechanism of action, and therapeutic potential is yet to be deciphered. For miR-199b, our ongoing studies have identified novel cooperating mutations that associate significant correlation with low miR-199b in AML and significantly affect the survival outcomes. Equally exciting are the outcomes from miR-199b knockout mouse model. For miR-125a, after defining its molecular basis of its epigenetic dysregulation and identifying potential targets via profiling studies in gain-of-function model, our ongoing studies are focused on determining its clinical significance and its action mechanism.
Novel Roles of Podocalyxin in Myelopoiesis and Myeloid Leukemia
Podocalyxin (PodxL) is a CD34 family member previously identified to mark hematopoietic stem cells (HSCs) and other progenitor cells. Previously, we discovered PodxL as a potent Erythropoietin (EPO) response gene and demonstrated to promote egression of immature reticulocytes from bone marrow into circulation. PodxL is upregulated in several cancers, including myeloid and lymphoid leukemia. Our lab discovered PodxL as a bona fide target of miR-199b. Current investigations aim to define the functional role of PodxL in hematopoiesis – specifically myelopoiesis – by employing conditional PodxL knock out (KO) mouse models where hematopoietic-specific deletion via Vav1-Cre driver and myeloid-specific deletion via Lyzm2 – Cre driver are being utilized.
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