NF-?B signaling pathway is one of the most extensively studied and understood pathways, however, the physiological impact of augmented NF-?B signaling in hematopoiesis has not been understood. Despite many recent studies documenting constitutive activation of NF-?B in patients with hematological disorders, including AML and MDS, it is remains unclear if constitutive NF-?B signaling is sufficient and/or necessary for the onset of the disease. Recently, we have shown that lack of A20 (a negative regulator of NF-?B) in hematopoietic stem cells (HSCs) causes loss of quiescence and severe hematologic abnormalities, due to constitutive NF-?B activation. In an attempt to decipher the role of NF-?B in HSCs, directly , we engineered mice to constitutively activate NF-?B in HSCs. Our preliminary data indicate that HSC quiescence and pool were completely lost, and that increased NF-?B signal alone was sufficient to disturb the transcriptional regulatory circuits of HSCs. In the proposed research, we would like to decode the potential molecular mechanisms through which increased NF-?B signals affect HSC biology. Our hypothesis is that deregulated canonical NF-?B signals impair hematopoietic stem cell (HSC) quiescence and functions by altering signal transduction pathways, `transcription factor networks' and expression of pro-inflammatory cytokines. To test this hypothesis, we will use a combination of genetic, molecular cell biology and biochemical approaches.
In specific aim 1, we will decipher the intrinsic mechanisms through which NF-?B affects HSC functions.
In specific aim 2, we will unravel the extrinsic role of NF-?B in the control of HSCs.
In specific aim 3, we would generate a novel humanized mouse model and decode the involvement of NF-?B signals in human HSC biology. We believe that the proposed research will provide key insights into the pathologic processes involving deregulated NF-?B signals, and will aid the development of newer and more successful therapies for human hematologic diseases that arise due to constitutive NF-?B activation.
Understanding pathways that regulate HSC quiescence may define potentially new targets for leukemia treatment and identify novel targets that prevent HSC exhaustion during pathological states. A clearer understanding on the precise role of NF-?B in HSCs would be essential to understand and treat hematopoietic diseases that arise due to defective NF-?B activation.