The overall objective of this proposal is to determine a potential of IEX-1 (Immediate Early responsive gene X-1) as a biomarker for the early diagnosis of myelodysplastic syndromes (MDS) or its progression to acute myeloid leukemia (AML). MDS is a clonal disorder of hematopoietic stem cells (HSCs) presumably resulting from the accumulation of mutations in genes that control the differentiation, self-renewal, or proliferation of HSCs. An unusual high frequency of genetic alterations in HSCs in MDS patients may be ascribed in part to increased production of reactive oxygen species (ROS) that causes DNA mutations, which could in turn lead to acquisition of additional genomic changes and ROS formation. IEX-1 takes part in regulating a balance between ROS generation and oxidative phosphorylation in mitochondria by targeting the inhibitor of mitochondrial FoF1-ATP synthase (IF1) to degradation. Over-expression of IEX-1 reduced the level of IF1 expression, concomitant with diminished ROS production, protecting cells from mitochondrion-dependent apoptosis. On the contrary, null mutation of IEX-1 stabilized IF1 expression and increased the susceptibility of cells to apoptosis. In accordance with a role of IEX-1 in the survival and differentiation of HSCs, IEX-1 deficient HSCs exhibited a high rate of apoptosis and proliferation but a decrease in their generation. Moreover, several studies recently showed that IEX-1 expression was deregulated in more than half of patients with MDS and the deregulation was correlated with the progression of the disease and the apoptosis level in CD34+ stem cells in the patients. Based on these observations, we hypothesize that deregulation of IEX-1 expression contributes significantly to the development of MDS and its progression to AML. We will test this hypothesis by long term competitive repopulation assays so as to determine whether or how IEX-1 contributes to MDS development via an autonomous or extrinsic fashion. The reconstituted mice will be then treated with anti-oxidant to restore the self-renewal capacity of HSCs.
In aim 2, we will expose IEX-1 knockout (KO) mice to radiation or chemotherapy that offers a """"""""second hit"""""""", rendering them more susceptible to radiation- or chemotherapy-induced DNA mutations and thus MDS/AML development. An increase in the susceptibility of IEX-1 KO mice to MDS/AML after the treatment will suggest that IEX-1 is one of the """"""""multiple hits"""""""" causing the genomic instability in HSCs and can be thus used as a biomarker for the prognosis of myeloid disorders. The study may also provide new insights into the mechanism for the disease development and help to develop novel strategies to prevent it.

Public Health Relevance

The study aims at determination of a role of IEX-1 in the survival and differentiation of bone marrow stem cells. Its deregulation may contribute to myelodysplastic syndromes (MDS) and progression of the disease to acute myelogenous leukemia (AML) and thus serves as a biomarker for early diagnosis and prognosis of the disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Molecular Oncogenesis Study Section (MONC)
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Sorbara, Lynn R
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Massachusetts General Hospital
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