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F-104 Decoding the regulatory networks of leukemic stem cells Through ubiquitylation

Rathinam, Chozha, PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2018 - Volume 77 - Issue - p 44
doi: 10.1097/01.qai.0000532613.57400.dc
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In the recent years, it has become increasingly evident that hematopoietic stem cells (HSCs) are directly involved in the recognition of both acute and chronic infections. HSCs sense immune insults by both cell intrinsic, through the pattern recognition receptors (PRRs), and extrinsic, mediated mainly by the pro-inflammatory cytokines, mechanisms. However, prolonged exposure of HSCs to inflammatory conditions results in defective differentiation of the immune cells. Even though earlier studies suggested that a tight control on inflammatory signals is essential for proper development of the immune system, precise molecular mechanisms that control inflammatory signals in HSCs and the effects of individual pro-inflammatory cytokines on HSC fate decisions have not been elucidated. In this study, we utilized several animal models including mice that either lack the ubiquitin editing enzyme-A20, that functions as a negative regulator of NF-κB, or express a constitutively active form of IKK2, which results in augmented NF-B signals, in the presence or absence of specific pro-inflammatory cytokines, to study the impact of inflammation in the determination of HSC fate. Our data indicate that deregulated NF-κB signals in HSCs lead to pathologic hematopoiesis, including a striking loss of lymphoid differentiation and skewing towards the myeloid lineage. Furthermore, NF-κB mediated lymphopenia was caused by both cell intrinsic (changes in genetic and molecular signatures) and extrinsic (elevated expression of pro-inflammatory cytokines) mechanisms. At this annual meeting, we would be discussing the precise molecular pathways through which inflammatory signals affect the development of Normal and Leukemic Stem Cells.

Institute of Human Virology, University of Maryland Baltimore School of Medicine

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