Glen D Raffel MD, PhD
|Institution||University of Massachusetts Medical School|
|Address||University of Massachusetts Medical School|
364 Plantation Street, LRB
Worcester MA 01605
|Institution||UMMS - Graduate School of Biomedical Sciences|
||1989||James Bowdoin Scholar|
|Bowdoin College||1989||Donald and Harriet Macomber Prize|
|Bowdoin College||1989||Summa cum laude in Biochemistry|
|Tufts University School of Medicine||1995||Allan MacLeod Cormack Award|
|Tufts University School of Medicine||1998||Alpha Omega Alpha|
|Tufts University School of Medicine||1998||William Dameshek Award in Internal Medicine|
|2002||Diplomate, Internal Medicine, American Board of Internal Medicine|
|2004||Diplomate, Medical Oncology, American Board of Internal Medicine|
|2005||Diplomate, Hematology, American Board of Internal Medicine|
The long-term ability of the body’s hematopoietic system to respond to hazardous stressors such as infection, bleeding or cytotoxic chemotherapy ultimately lies with the function of the hematopoietic stem cell (HSC). The defining property of the HSC is self-renewal, allowing replenishment of the cellular blood components over a lifetime. Long-term self-renewing HSCs are maintained in the quiescent G0 phase of the cell cycle through a complex interaction with the bone marrow niche. During proliferative stress, HSCs must enter the cell cycle to generate differentiated progeny to supply the body’s demands. Afterwards, HSCs must be able to return to quiescence, otherwise they will be depleted, leading to bone marrow failure and death. Therefore, pathways controlling the balance between HSC quiescence and proliferation are critically important and tightly regulated. Conversely, these same pathways are often dysregulated in hematopoietic malignancies.
The OTT1(aka RBM15) gene was originally isolated as the 5’ fusion partner in the t(1;22)(p13;q13) translocation associated with infant acute megakaryocytic leukemia (AMKL). OTT1 is an ubiquitously expressed member of the spen family of developmental regulators, which are defined by the presence of three RNA-recognition motifs (RRM) and a spen paralog and ortholog (SPOC) domain. Ott1 is believed to be involved with alternative RNA splicing and nuclear export. The SPOC domain confers transcriptional activation/repressor function via an associated Hdac/Ncor/Smrt/Setd1b complex towards currently unknown native targets. A third domain is able to bind the Notch effector, Rbpj, and has been found to activate or repress Notch downstream effectors in a cell context-dependent manner. Constitutive activation through the Notch-effector, RbpJ?, contributes in part, to the oncogenic activity of the t(1;22) fusion product, OTT1-MAL.
Using a conditional knockout approach in mice and deletion within the hematopoietic compartment, we demonstrated Ott1 has a significant role as a global hematopoietic regulator. Ott1 is required for pre-B development and has inhibitory roles in megakaryocyte, granulocytes and granulocyte/monocyte progenitor development. Although HSC populations are expanded in number after deletion, competitive repopulation experiments showed the HSCs were defective, thus demonstrating that Ott1 is required for HSC function. Further investigations revealed Ott1 is dispensable during steady-state hematopoiesis, however, it is required to maintain quiescence/self-renewal during proliferative stress. We have uncovered roles for Ott1 in the regulation of several processes critical to HSC function including quiescence, control of ROS, stress response and mitochondrial biogenesis. In addition, Ott1-deficient HSCs share many characteristics of prematurely aged HSCs, raising the possibility of Ott1-dependent control of aging-related pathways. The developmental requirement for Ott1 in other tissues such as heart and spleen and its near ubiquitous expression suggest these Ott1-dependent processes may play a more expansive role than confined to hematopoiesis.
The ability to pharmacologically manipulate HSCs to expand, preserve self-renewal or better tolerate stress is a sought-after goal that would have far-reaching clinical benefits. HSC transplantation is limited by the quantities of available donor cells, particularly from umbilical cord sources, thus enabling in vitro graft expansion while preserving self-renewal capability would be invaluable. HSC exhaustion during cytotoxic chemotherapy is a major dose-limiting toxicity associated with considerable morbidity and mortality especially in the elderly. Likewise, HSCs in inherited and acquired bone marrow failure syndromes are unable to respond adequately to stressors such as infection or anemia.
We are pursuing the molecular basis underlying the critical functions of Ott1 in hematopoietic and other tissues and how those functions are co-opted in t(1;22) AMKL. Ott1 is involved in control of transcription and splicing and our focus is to ascertain the targets with the aid of mouse genetic models. Our goal is to identify Ott1-dependent pathways important to HSC function to allow development of therapeutic interventions to guard HSC function during stress and impair function in malignant cells.
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