Roland Jurecic, Ph.D.
Associate Professor of Microbiology and Immunology, and Cell Biology and Anatomy
Description of Research
1. The heterogeneity and metastability of HSCs
Newly discovered phenotypic and functional heterogeneity among HSCs, with co-existence of several HSC subsets with different self-renewal and differentiation capacities is shifting our perception of HSCs from being a functionally uniform pool to a dynamic pool of multiple HSC subsets. Dr. Jurecic’s laboratory discovered that HSCs oscillate between slowly cycling metastable subsets which are in a self-renewal state and actively cycling metastable subsets that are both self-renewing and ready to differentiation. These metastable states are characterized by distinct expression of HSC markers, cell cycle profiles, expression of activated signal transduction molecules, and differentiation patterns. Their findings support the notion that the metastability enable HSCs to alternate between self-renewing states and states in which HSCs are both self-renewing and differentiating.
2. Molecular pathways that regulate HSC self-renewal and differentiationDr. Jurecic reported that E3 ubiquitin ligase Rnf41 regulates differentiation of HSCs and progenitors by governing steady-state levels of receptors for cytokines and RA receptor RAR alpha. Through over-expression and knockdown approaches Dr. Jurecic's laboratory is studying further the role of Rnf41 in regulating differentiation of mouse and human HSCs and progenitors.
Dr. Jurecic has discovered that besides c-kit, HSCs express new intracellular truncated form of c-kit, called tr-kit. They reported that tr-kit transcript and protein are rapidly down-regulated during cytokine induced differentiation of HSCs. Using a variety of approaches Dr. Jurecic's laboratory is exploring in depth the role of tr-kit and associated pathway(s) in HSC self-renewal and differentiation.
3. The Mechanisms of Development of RA-resistant Acute Promyelocytic Leukemia
While the treatment with high doses of all-trans RA often induces differentiation of APL cells (RA-sensitive APL), ~30% of APL patients develop RA-resistant APL, characterized by the significant decrease or loss of PML/RAR<&alpha> protein expression due to its degradation via ubiquitin pathway. However, the mechanisms of degradation of PML/RAR alpha and development of RA-resistant APL are not well understood. Since the PML/RAR alpha negatively regulates expression of E3 ubiquitin ligase RNF41 in human hematopoietic progenitors, and the RNF41 expression is down-regulated in RA-sensitive APL cells, in this project Dr. Jurecic's laboratory is investigating if RNF41 contributes to development and/or maintenance of RA-resistant APL through degradation of PML/RAR alpha oncoprotein.
4. Acute and delayed effects of ionozing radiation of the hematopoietic system and HSCs, and mitigation of early and late effects of radiation on HSC function.
IR induces acute and chronic inflammation, and casues oxidative stress and DNA damage (DNA double-strand breaks) in HSCs via significant elevation of intracellular levels of reactive oxygen species (ROS) and increased production of ROS by inflammatory leukocytes. This leads to accumulation of missrepaired DNA damage and permanent genomic modifications, which may contribute to the functional impairment and genetic instability of HSCs. The development of agents that can reduce IR-induced inflammatory injury and oxidative DNA damage could have an important impact on treatment of patients undergoing radiation and treatment of radiation injuries due to a nuclear accident or attack.
In this NIH-funded project, Dr. Jurecic's laboratory is testing whether delayed treatment with Leukadherins, a novel class of compunds with anti-inflammatory and immunosuppressive properties, can effectively mitigate the adverse effects of IR on the hematopoietic system and HSCs by reducing inflammatory injury.
- Discovery of Pum genes as an evolutionarily conserved intrinsic mechanism that supports the self- renewal of HSC and multipotent progenitors
- Discovery of a new E3 ubiquitin ligase that affects proliferation and differentiation of HSC and multipotent progenitors by regulating steady-state cytokine receptor levels through ligand-independent degradation, and that may be involved in etiology of hematological malignancies
- Discovery of a new intracellular truncated form of c-kit, called tr-kit, which is involved in regulation of HSC and MPP differentiation
- Finding that Wnt5a gene negatively regulates B cell proliferation, and that inactivation of Wnt5a leads to development of myeloid leukemias and B cell lymphomas
- Discovery of the deletion of the WNT5a gene and/or loss of WNT5a expression in human primary leukemias, demonstrating for the first time that WNT5a gene functions as a tumor suppressor