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Importance of Bcl-2-family proteins in murine hematopoietic progenitor and early B cells.

ABSTRACT: Mitochondrial apoptosis regulates survival and development of hematopoietic cells. Prominent roles of some Bcl-2-family members in this regulation have been established, for instance for pro-apoptotic Bim and anti-apoptotic Mcl-1. Additional, mostly smaller roles are known for other Bcl-2-members but it has been extremely difficult to obtain a comprehensive picture of the regulation of mitochondrial apoptosis in hematopoietic cells by Bcl-2-family proteins. We here use a system of mouse 'conditionally immortalized' lymphoid-primed hematopoietic progenitor (LMPP) cells that can be differentiated in vitro to pro-B cells, to analyze the importance of these proteins in cell survival. We established cells deficient in Bim, Noxa, Bim/Noxa, Bim/Puma, Bim/Bmf, Bax, Bak or Bax/Bak and use specific inhibitors of Bcl-2, Bcl-X_L and Mcl-1 to assess their importance. In progenitor (LMPP) cells, we found an important role of Noxa, alone and together with Bim. Cell death induced by inhibition of Bcl-2 and Bcl-X_L entirely depended on Bim and could be implemented by Bax and by Bak. Inhibition of Mcl-1 caused apoptosis that was independent of Bim but strongly depended on Noxa and was completely prevented by the absence of Bax; small amounts of anti-apoptotic proteins were co-immunoprecipitated with Bim. During differentiation to pro-B cells, substantial changes in the expression of Bcl-2-family proteins were seen, and Bcl-2, Bcl-X_L and Mcl-1 were all partially in complexes with Bim. In differentiated cells, Noxa appeared to have lost all importance while the loss of Bim and Puma provided protection. The results strongly suggest that the main role of Bim in these hematopoietic cells is the neutralization of Mcl-1, identify a number of likely molecular events during the maintenance of survival and the induction of apoptosis in mouse hematopoietic progenitor cells, and provide data on the regulation of expression and importance of these proteins during differentiation along the B cell lineage.

SUBMITTER: Kurschat C

PROVIDER: S-EPMC8358012 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Scientific investigations designed to better understand and assess the distinguishing clinical characteristics pave the way to a successful treatment for a disease. Since the peripheral blood is obtained easily, the most frequent type of investigation performed on infectious agents focuses on the hematological components of blood drawn from patients. Bone marrow aspirates, although somewhat more difficult to obtain, should be evaluated more frequently because they provide additional information, giving us a glimpse into the development of the disease. Understanding the distinct and unique changes in hematological components of the bone marrow induced by a particular pathogen or corresponding to a specific illness may be a valuable asset for the diagnosis and prognosis of disease. A good example of a pathogen that could be better evaluated with greater knowledge of the bone marrow is dengue, one of the most important public vector-borne human diseases. Owing to the multitude of clinical manifestations and the dynamic alterations of various blood components over time, this disease is one of the most difficult to prevent and treat in humans. Although large amounts of data have been generated in the literature, there remains a large gap between this information and its relevance for the purpose of patient care. While evaluating the cellular components in the circulated blood from ill patients provides us with valuable information about the pathogenesis of various pathogens, there are other players participating in the progression to disease. The goal of this review is to emphasize the importance of bone marrow hematopoietic progenitor cells in disease and to inspire other researchers to incorporate them into their investigations on dengue pathogenesis. It is anticipated that the knowledge derived from these investigations not only elicit original concepts on the pathogenesis of dengue but also foster a new way of thinking in terms of vaccine or therapeutic development to prevent and treat dengue.

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Importance of Bcl-2-family proteins in murine hematopoietic progenitor and early B cells.

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