title: Replenishment of the B cell compartment after doxorubicin-induced hematopoietic toxicity is facilitated by STAT1.
abstract: STAT1 serves as an important regulator in the response to pathogens, oncogenic transformation, and genotoxic insults. It exerts these effects by shaping the innate and adaptive immune response and by participating in genotoxic stress pathways, leading to apoptosis and inhibition of cell proliferation. We have investigated the role of STAT1 in hematopoietic toxicity induced by doxorubicin in STAT1-proficient and -deficient mice. Whereas the early genotoxic effect of doxorubicin did not depend on STAT1, expression of STAT1 was required for efficient B lymphocyte repopulation in the recovery phase. We found a lower abundance of lymphocyte precursors in the BM of STAT1-deficient animals, which was particularly evident after doxorubicin-induced hematopoietic toxicity. In accordance, colony-forming assays with STAT1-deficient BM cells revealed a decreased number of pre-B colonies. Differentiation from the pro-B to the pre-B stage was not affected, as demonstrated by unaltered differentiation of purified B cell precursors from BM in the presence of IL-7. With the exception of Sca-1, expression of genes implicated in early lymphocyte development in pro-B cells did not depend on STAT1. Our findings indicate a specific requirement for STAT1 in lymphoid development before differentiation to pre-B cells, which becomes particularly apparent in the recovery phase from doxorubicin-induced hematopoietic toxicity.
authors.affiliation: Medical Biochemistry.
authors.forename: Sebak
authors.initials: S
authors.lastname: Datta
authors.affiliation: Medical Biochemistry.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Parajuli
authors.affiliation: Medical Biochemistry.
authors.forename: Piotr
authors.initials: P
authors.lastname: Tymoszuk
authors.affiliation: Developmental Immunology.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ottina
authors.affiliation: Institute of Legal Medicine, and Pennsylvania State Eberly College of Science, University Park, Pennsylvania, USA.
authors.forename: Walther
authors.initials: W
authors.lastname: Parson
authors.affiliation: Experimental Pathophysiology and Immunology, Innsbruck Medical University, Austria; and.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Sgonc
authors.affiliation: Developmental Immunology.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Medical Biochemistry, wolfgang.doppler@i-med.ac.at.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Doppler
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000950:Antigens, Ly / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D004317:Doxorubicin / Q000633:toxicity*; D006410:Hematopoiesis / Q000187:drug effects; D007371:Interferon-gamma / Q000502:physiology; D015851:Interleukin-7 / Q000494:pharmacology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D050794:STAT1 Transcription Factor / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000950:Antigens, Ly; D015851:Interleukin-7; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D004317:Doxorubicin; D007371:Interferon-gamma
keywords: IFN-γ; IL-7; Sca-1; lymphocyte development; pro-B cells