Young Investigator Grants

Myelodysplastic syndrome are a collection of clonal haematopoietic stem cell (HSCs) disorders with very limited treatment options. We hypothesise that a combination of aging and genetic abnormalities in HSCs transmit disease cues to the bone marrow niche that in-turn provides nurturing signals for the sustenance of the disease. A combination of xenotransplantation, RNA sequencing and cytokine profiling will be used to delineate the interacting surface proteins between the MDS HSCs and niche mesenchymal stromal cells. Large-scale siRNA screening followed by targeted inducible shRNA lentiviral approach will be used to identify the receptor-ligands that can be potentially used as therapeutic targets.

MDS arises from the accumulation of mutations in hematopoietic stem cells (HSC’s) & therapy resistance is invariable. We identified significant upregulation, increased expression of STAT3 in MDS-HSC’s that was predictive of adverse prognosis. KTX-21 & KTX-105 are two specific STAT3 degraders that decreased cellular proliferation, and caused significant downregulation of STAT3 as well as its target genes (MCL1) in multiple hypomethylating agent and venetoclax resistant leukemic lines. In Aim 1, we test the efficacy of the STAT3 degraders by treating a large cohort of therapy resistant primary patient samples and PDX’s. In Aim 2 we will evaluate the preclinical efficacy of STAT3 degradation alone and in combination with the clinically relevant MCL1 inhibitor AZD5991 in therapy resistant MDS.

Clonal hematopoiesis is a common and potentially targetable condition defined by the expansion of blood cells carrying mutations in leukemia-associated genes. This condition occurs more frequently with increasing age and after chemotherapy exposure where it is a strong risk factor for therapy-related myeloid neoplasms. Chemotherapy contributes to an inflammatory bone marrow microenvironment that selects for leukemogenic clones. Therapeutic targeting of the inflammatory microenvironment could reduce the risk of further clonal evolution to frank malignancy. We will investigate the effects of metformin on therapy-related clonal hematopoiesis and its impact on clinical outcomes in a high-risk group of breast cancer survivors.

Genes encoding RNA splicing factors are common mutational targets across myeloid neoplasms. This proposal will focus on a specific form of spliceosomal gene mutations which has received relatively little study and for which we have developed substantial novel reagents and preliminary data. Specifically, we aim to systematically determine the mechanistic, functional, and therapeutic consequences of ZRSR2 mutations in myeloid leukemias. As such, we expect our studies to provide novel insights into the biology of myeloid malignancies driven by spliceosomal gene mutations and uncover novel, mechanism-based therapeutic approaches for MDS and AML patients bearing ZRSR2 mutations.

The implementation of next generation sequencing has greatly influenced diagnostic, prognostic, and therapeutic decisions in MDS. From these studies, recent investigations have suggested that the mutational status of TP53 is the most important negative prognostic factor in MDS patients. Specifically, TP53 mutations predict for a median overall survival of 6-12 months with inferior outcomes to hypomethylating agents and allogeneic hematopoietic stem cell transplantation. Furthermore, we have identified that the variant allele frequency of TP53 is integrally related to patient outcomes. Together, these studies highlight the profound negative consequence of TP53 mutation in MDS and the need for effective targeted therapies.

Myelodysplastic syndromes (MDS) are heterogeneous clonal disorders which are characterized by ineffective hematopoiesis and uni- or multi-lineage dysplasia. Although many genetic and epigenetic aberrations have been identified, the clinical features remain common. We have found that hypoxia inducible factor-1α (HIF-1α) signature is widely activated in MDS patients. Using inducible HIF-1α transgenic mice and our new MDS mouse models, we are elucidating the essential and sufficient roles of HIF-1α for developing MDS development. The goal of this project is to clarify the significance of HIF-1α for the pathogenesis of MDS and validate HIF-1α as a therapeutic target for MDS.

Because of their short half-life, millions of mature blood cells are continuously replenished from a rare population of hematopoietic stem cells. Understanding the precise mechanisms involved in this process is of considerable relevance for human health and disease, as these regulatory stages frequently are hijacked in hematologic malignancies. More than 90% of human genes undergo alternative splicing, which can generate multiple isoforms with different functions from individual genes, adding further complexity to the regulation of gene function. Recent identification of recurrent mutations in genes involved in mRNA splicing in patients with hematopoietic malignancies, in particular in myelodysplastic syndromes, implicates alternative splicing as an important regulator of normal blood development and leukemic transformation. The proposed research program is focused on first characterizing the extent of alternative isoform usage during the earliest stages of normal blood differentiation, and how this impacts the ability of rare hematopoietic stem cells to generate mature blood cells in both mouse and man. Secondly, the impact of mRNA splicing on blood development will be investigated by knocking out components of the mRNA splicing machinery. And finally, we will investigate the impact of recurrent mutations in the splicing machinery during distinct stages of blood development in order to understand how these mutations contribute to establish and propagate MDS disease. Importantly, this has translational importance, considering the high frequency of mutations targeted to the splicing machinery in hematologic malignancies, as well as in relationship to the need to develop more targeted therapies aimed at eliminating the propagating leukemic stem cells.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases marked by ineffective hematopoiesis with bone marrow (BM) hyperplasia and blood cytopenia. Molecular pathogenesis of MDS remains incompletely understood with limited therapeutic options. Our recent genomic investigations of MDS found that ZRSR2 gene is mutated in 3-10% of MDS samples which impairs its normal function. Our experiments demonstrate that ZRSR2 protein is required for RNA processing in the clels, and that ZRSR2 is important for hematopoietic differentiation. Our objective, using ZRSR2 as a focus, is to discover how aberrant RNA processing plays a role in the pathogenesis of MDS and to provide a mechanistic foundation for the development of therapies targeting the spliceosome machinery in MDS.