I will represent new work from our group on the identification of novel checkpoint genes in hematopoietic stem cells in response to telomere dysfunction

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Simposio Internacional: Los próximos 20 años en la investigación de los telómeros International Symposium: The Next 20 Years of Telomere Research

Madrid, 15 y 16 de noviembre de 2011 Madrid, November 15-16, 2011

FUNDACIÓN RAMÓN ARECES

ABSTRACT- K. Lenhard Rudolph

Identification of a differentiation checkpoint limiting self-renewal of hematopoietic stem cells in response to telomere dysfunction

Stem cells are present in most adult mammalian tissues and organs and contribute to lifelong maintenance and repair of tissues and organs. There is emerging evidence that the functional capacity of stem cells declines during organismal aging possibly contributing to the age dependent decline in organ function and the increasing cancer risk. The accumulation of DNA damage represents one molecular mechanisms contributing to the aging process and DNA damage also accumulates in aging stem cells. Telomere shortening represents a cell intrinsic mechanism, which can contributes to the accumulation of DNA damage in aging cells. I will represent new work from our group on the identification of novel checkpoint genes in hematopoietic stem cells in response to telomere dysfunction. To this end we conducted functional genomic siRNA screens targeting tumor suppressor genes. Transduced hematopoietic stem cells were transplanted into lethally irradiated recipients. Deep sequencing analysis was used for the identification of siRNA constructs that were positively selected in telomere dysfunctional HSCs compared to wildtype HSCs. This screen led to the identification of a novel checkpoint limiting maintenance of HSCs in response to DNA damage. The study shows that DNA damage induces lymphoid differentiation of HSCs possibly contributing to the depletion of lymphoid competent HSCs with aging. An analysis of human HSCs indicates that the checkpoint could be conserved in humans. We propose that damage induced differentiation of stem cells may represent a novel checkpoint layer to limit cancer formation in aged tissues.

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