Cytokines, such as erythropoietin, interleukins and thrombopoietin, control the development and physiology of hematopoietic lineages. Notably, aberrant cytokine signalling has been associated with the initiation and/or progression of leukemias. Upon binding of cytokines to their respective receptors several signalling pathways are activated that elicit various cellular responses, including proliferation, differentiation, survival and death. The majority of cytokines activate pathways that utilize the transcription factors STAT5a and STAT5b (STAT5). In fact, aberrant activation of STAT5 has been observed in leukemias, which suggests that it plays a critical role in disease progression. Deletion of the transcription factor STAT5 from the mouse genome results in multiple defects in many organ systems, emphasizing a crucial role of cytokines in a number of different cell types. Researchers in LGP in collaboration with other scientists have used mice from which the Stat5 genes had been deleted either from the germline or from specific cell types to explore the mechanisms by which Stat5 controls normal and neoplastic hematopoiesis. Our findings demonstrated a critical role of STAT5 in the function of the immune system (B and T cells) and in some myeloid disorders. ? ? During this reporting period progress has been made in our understanding on how the transcription factor STAT5 controls erythropoiesis and contributes to certain leukemias. Moreover, knowledge has been gained in the mechanisms imposed by the STAT-SOCS network on B lymphopoiesis.? ? Erythropoiesis? Erythropoietin (Epo) controls the development of red cells and it has been established that the STAT5 signaling pathway is activated upon the binding of Epo to its cognate receptor. Several years ago LGP scientists deleted the Stat5 genes from the mouse genome (Cui et al., 2004) and they discovered that these mice were severely anemic and died perinataly. Although we were able to link Stat5 to normal erythropoisis, a mechanistic link was not established. LGP scientists have now identified one of the mechanisms used by STAT5 to control erythropoiesis. We have discovered that STAT5 controls iron metabolism in red cells (Zhu et al., 2008). This paper was highlighted in an editorial in the Journal BLOOD. In particular, our research demonstrated that STAT5 mediates transcription of the transferrin receptor gene, which is subsequently impaired in the absence of STAT5. Loss of STAT results in impaired iron absorption and microcytic anemia. ? ? Leukemia? One class of leukemias is characterized by mutations that result in the truncation of the G-CSF receptor (Csf3r). Patients carrying these mutations develop severe congenital neutropoenia. We have discovered that leukemic mutations in the Csf3r result in a clonalk advantage of mutant hematopoietic stem cells (HSC) and that this is controlled by STAT5. In the absence of STAT5 mutant HSCs lose the clonal growth advantage. This study revelealed that STAT5 could be a promising target to combt this class of leukemia. This paper (Liu et al., 2008) was accompanied by an editorial in JCI that highlighted its implications for translational research.? ? B Lymphopoiesis? It was known that chemokines control bone marrow progenitor B cells but the context within the cytokine network was elusive. To address this missing link we have disturbed cytokine signaling in B cells through the deletion of SOCS3, a key regulator of STAT signaling. Using these mice, as well as cells derived from them, we were able to demonstrate that SOCS3 regulates chemokine (CXCL12) induced FAK phosphorylation through the ubiquitin-proteasome pathway. This work links chemokines and SOCS3 to the lodgement of B cell precursors in the bone marrow microinvironment.
