Collaboration between DNA damage and immune responses in leukemic stem cell emergence and expansion
Acute Myeloid Leukemia (AML) has a 5-year survival rate of 25%. Thus, clinical evidence continues to support the need to identify novel targets and therapeutics for the treatment of this deadly disease. Experimental evidence has clearly shown that interaction of the leukemic cell with the tumor microenvironment (TME) contributes to de novo drug resistance and likely failure to eliminate minimal residual disease (MRD). It is currently less clear what the impact of TME-induced expansion of regulatory T cells (Tregs) in mediating MRD following standard of care treatment and bone marrow (BM) transplant. We will utilize a model of Fanconi anemia (FA), a cancer-prone disease with extremely high incidence of myelodysplastic syndrome (MDS) and AML, to determine the role of the TME in the expansion of the Treg population, relapse and progression of AML.
People who work on this project: Limei Wu; Shaina Kopelov; Allison Cole
Hematopoietic stem cell polarity in bone marrow failure and leukemia
Stem cell and gene therapies through hematopoietic stem cell transplantation (HSCT) is the only definite treatment for various hematological malignancies, including FA. However, three major hurdles have been hampering scientific and clinical advance in the blood cancer HSCT field: 1) ineffective mobilization of patient stem cells; 2) hypersensitivity of recipient patients to pre-conditioning regimens; and 3) inefficient delivery of donor stem cells to the BM of cancer patients. Therefore, there is a great need to develop novel pre-conditioning agents that can optimize homing and entry of HSCs into recipient BM niche with minimal toxicity. The project will examine the mechanistic link between stem cell polarity, and HSC renewal and engraftment defects. Further, an innovative xenotransplant model will be employed to determine the potential of targeting stem-niche interaction in stem cell and gene therapies.
People who work on this project: Jian Xu; Frank Oley; Zachary Sherman; Allison Cole
PARP-NHEJ interaction in cancer drug resistance
Compelling evidence suggested that the FA pathway promotes the error-free homologous recombination (HR) repair pathway while suppressing the error-prone non-homologous end-joining (NHEJ) pathway, likely through preventing inappropriate recruitment of NHEJ factors to sites of DNA damage. However, the exact mechanism by which the FA pathway counteracts the NHEJ pathway is largely unknown. PARP1 is a major DNA damage response protein primarily involved in the base excision repair (BER) pathway. It has been shown that PARP inhibitors could selectively target cancer cells with a defective HR repair of DSB, such as BRCA1-, BRCA2-, and ATM-deficient cells, by inducing genomic instability and eventual cell death due to the development of non-viable genetic errors generated by the error-prone NHEJ repair. We will investigate the mechanism by which FA leukemia develops resistance to synthetic lethality induced by PARP inhibition. Furthermore, FA AML xenotransplant model will be used to define the role of synthetic lethality resistance in leukemia relapse.
People who work on this project: Jian Xu; Limei Wu; Allison Cole