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

The JAK-STAT pathway is a rapid signaling pathway downstream of cytokine and growth factor receptors, required to change gene regulation [1]. JAKs activate one or several members of the seven STAT transcription factors, and they control cell growth, survival, and differentiation, but they also drive different cancer types. Scientific merit comes from new STAT1 findings using WT or Stat1-deleted mice analyzing hematopoiesis before and after chemotherapeutic drug application (Fig. 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. The JAK-STAT pathway gained increased attention in the last years as a result of persistent activation found in all four JAK family members [1]. Hyperactive JAKs promote STAT transcription factor activation via tyrosine phosphorylation in neoplastic cells. STAT1 is an essential transcription factor for innate and acquired immunity, as revealed by lossor gain-of-function mutations found in patients [3]. It was cloned in 1992, and the function of STAT1 is closely associated with JAK1 and TYK2 signaling [4]. TYK2 was the last JAK family member, where recently activating mutations were discovered in T cell acute lymphoblastic leukemia [5]. Here, an oncogenic TYK2-STAT1-BCL2 axis was found to be associated with intracellular IL-10 signaling. Many important functions of STAT1 are attributable to IFN signaling, e.g., for defense against infectious disease, but STAT1 function was also linked to the suppression of cancer cell growth, immunoediting/immunosurveillance, or cancer cell apoptosis. The role of STAT1 as a tumor suppressor is widely accepted, as it can induce cell-cycle inhibitors or caspase genes, but STAT1 also regulates MHC class I expression, thereby regulating acquired immunity. Furthermore, macrophages and NK and T cells were shown to rely on STAT1 for effector functions. Notably, STAT1 proteins also have important functions in the non-tyrosine phosphorylated state (U-STAT1) as transcription factors and modifiers of other transcription factors [6, 7]. STAT1 was found persistently in the nucleus without the prerequisite of tyrosine phosphorylation. U-STAT1 prolongs the expression of a subset of IFN-induced genes, in particular, if expressed to high levels. An essential role for STAT1 in differentiated myeloid cell types, such as erythrocytes or megakaryocytes [8, 9], and in type I IFN-induced hematopoietic stem cell activation and cycling [10] was demonstrated. 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. 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. Doxorubicin treatment triggers strong myelosuppression in mice, but the authors extend on doxorubicin impact on blood cells with detailed immunophenotyping and functional analysis. They found a profound general hematopoietic defect in mice devoid of STAT1, particularly evident in decreased common lymphoid progenitor numbers or toxicity, therein upon doxorubicin treatment. 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