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.

Combination of glycosphingosomes and liposomal doxorubicin shows increased activity against dimethyl-α-benzanthracene-induced fibrosarcoma in mice

“…18,28,29 The administration of Dox has been shown to cause toxicity and the depletion of leukocytes. 31,32 The results of the present study showed that free Dox induces both quantitative and qualitative changes in the leukocytes. The group of mice treated with free Dox exhibited a substantial reduction in leukocyte count compared to the groups injected with Lip-Dox or a combination of Lip-Dox and glycosphingosomes.…”

Editorial: Recovery from chemotherapy depends on STAT1 for replenishment of B lymphopoiesis

“…1). The team of Wolfgang Doppler and colleagues [2] focused on basic and preclinical cancer research questions and consequences for the hematopoietic system upon anthracycline treatment. This work will be placed in context below, but we highlight first the JAK-STAT pathway in association with cancer research.…”

“…No obvious defects in B lymphopoiesis were described to date. It was so far poorly characterized that STAT1 is also required for normal hematopoietic cell development and maintenance of homeostasis, and a role especially upon hematopoietic challenge, e.g., after chemotherapy, has now been reported by Datta et al [2]. A role for STAT1 upon response to various chemotherapeutic drugs was recognized early in human cancer cell line studies, but in vivo animal studies with genetic loss of Stat1 proving this concept were lacking.…”

“…A role for STAT1 upon response to various chemotherapeutic drugs was recognized early in human cancer cell line studies, but in vivo animal studies with genetic loss of Stat1 proving this concept were lacking. The approach being taken by Datta et al [2] involved cohorts of mice exposed to doxorubicin treatment. Competitive bone marrow transplantation, detailed immunophenotyping, flow cytometry, and immunohistochemistry of B cells in lymphoid organs were carried out.…”

“…It will be interesting to test other chemotherapeutic regimens in the presence or absence of STAT1. Datta and colleagues [2] discovered in their work a new role for STAT1 signaling for B lymphopoiesis under steady-state conditions and myeloablation. STAT1 deficiency mildly increased myelopoiesis, but particularly, B lymphoid development was blunted and depended on STAT1 during normal hematopoiesis or upon chemotherapeutic challenge.…”