The Intrinsic Apoptotic Cascade in Hematopoiesis and Susceptibility to Therapy-Related Leukemia.

摘要

Apoptosis and the DNA damage response have been implicated in hematopoietic development and differentiation, as well as in the pathogenesis of myelodysplastic syndrome (MS) and leukemia. However, the specific roles of direct mediators of apoptosis, such as caspases, in hematopoiesis and leukemogenesis have not been elucidated. In order to address this, we studied the effects of loss of Caspase-9, the initiator caspase of the intrinsic apoptotic cascade, and Apaf1, the key component of the apoptosome, on fetal and adult hematopoiesis. We first found that loss of these key regulators has significant effects on the hematopoietic stem and progenitor compartment, with decreases in erythroid and B-cell progenitor abundance and impaired function of hematopoietic stem cells after transplantation. Long term adult hematopoiesis is also altered in bone marrow chimeras lacking Casp9 and Apaf1. Counter-intuitively, mice lacking these cell death components show low white blood cell counts, decreased B cell abundance and anemia. Ultimately, they die early due to bone marrow failure.;Defects in apoptosis have also been previously implicated in susceptibility to therapy-related leukemia, a disease caused by exposure to DNA-damaging chemotherapeutics used as treatment for other malignancies. Decreased apoptosis could allow cells to inappropriately survive exposure to DNA damaging agents, giving rise to a population of cells with increased DNA damage that was more prone to clonal outgrowth or malignant transformation. We examined whether loss of Casp9 or Apaf1 altered response to N-ethyl-nitrosurea (ENU), an alkylator similar to those used in chemotherapy, and found that loss of these genes did result in increased DNA damage in surviving cells after ENU-treatment. Furthermore, exome sequencing revealed that loss of Casp9 when combined with alkylator treatment gives rise to oligoclonal hematopoiesis, a precursor to diseases such as MDS and acute myeloid leukemia. Taken together these findings suggest that loss of apoptosis could be a key step in the pathogenesis of therapy-related disease.