STAT5 Activation Underlies IL7 Receptor-Dependent B Cell Development

Abstract

Signals initiated by the IL7R are required for B cell development. However, the roles that distinct IL7R-induced signaling pathways play in this process remains unclear. To identify the function of the Raf and STAT5 pathways in IL7R-dependent B cell development, we used transgenic mice that express constitutively active forms of Raf (Raf-CAAX) or STAT5 (STAT5b-CA) throughout lymphocyte development. Both Raf-CAAX and STAT5b-CA mice exhibit large increases in pro-B cells. However, crossing the Raf-CAAX transgene onto the IL7R−/− background fails to rescue B cell development. In contrast, STAT5 activation selectively restores B cell expansion in IL7R−/− mice. Notably, the expansion of pro-B cells in STAT5b-CA mice correlated with an increase in cyclin D2, pim-1, and bcl-xL expression, suggesting that STAT5 directly affects pro-B cell proliferation and survival. In addition, STAT5 activation also restored B cell differentiation in IL7R−/− mice as determined by 1) the restoration of VH Ig gene rearrangement and 2) the appearance of immature and mature B cell subsets. These findings establish STAT5 as the key player entraining B cell development downstream of the IL7R.

Ig Gene Rearrangement Steps Are Initiated in Early Human Precursor B Cell Subsets and Correlate with Specific Transcription Factor Expression

“…This could indicate that higher levels of the recombinase machinery are needed for initiation of V H to DJ H gene rearrangements. In mice, IL-7R signaling induces V H -DJ H rearrangements via STAT5 activation (46). STAT5B gene expression was indeed up-regulated in human pre-B-I cells, but IL7RA was not expressed before the stage of large pre-B-II cells.…”

Constitutive STAT5 activation specifically cooperates with the loss of p53 function in B-cell lymphomagenesis

“…Recent analyses of mice expressing a transgene encoding the constitutively active STAT5B(H299R/ S711F) mutant reported several alterations in lymphoid cell development and homeostasis (Burchill et al, 2003;Goetz et al, 2004). Transgenic STAT5A* mice showed similar developmental defects, although with lower penetrance.…”

“…An hypomorphic STAT5A and B loss of function mutant shows that these proteins also play a redundant role in the response of hematopoietic cells to a wide variety of cytokines and result in a dramatic decrease in stem-, multipotent and lineage-committed progenitors (Teglund et al, 1998;Bunting et al, 2002;Snow et al, 2002). The study of this loss of function mutant mouse and of transgenic mice with lymphoidspecific targeting of STAT5A or B have identified critical roles of STAT5 in interleukin (IL)-7 receptor signaling in both fetal thymocyte and early B-cell progenitor development (Sexl et al, 2000;Burchill et al, 2003;Goetz et al, 2004Goetz et al, , 2005Kang et al, 2004), in cytokine-induced proliferation of peripheralactivated T cells and memory T cells (Burchill et al, 2003;Kelly et al, 2003a;Moriggl et al, 1999) and in the development of CD4 þ CD25 þ regulatory T cells and natural killer-T cells (Burchill et al, 2003).…”

Ebf1orPax5haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

“…1 µl of cDNA template was used in a 20 µl reaction. Primers for Ebf1, Pax5, and Hprt have been previously described (Goetz et al, 2004). Reactions using Platinum quantitative PCR SuperMix-UDG with ROX were set up according to the instructions provided by the manufacturer (Invitrogen) and performed on a 7000 Sequence Detection PCR System (Applied Biosystems).…”