STAT5 in B cell development and leukemia

Malin, Stephen; McManus, Shane; Busslinger, Meinrad

doi:10.1016/j.coi.2010.02.004

Cited by 71 publications

(73 citation statements)

References 75 publications

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“…In response to IL-7 signals, STAT5 regulates the survival and proliferation of B-cell progenitors and plays an important role in the generation of B-cell leukemia and lymphoma [36,42]. Notably, both BCR and IL-7 signals regulate the expression of Rag proteins via the PI3K/Akt/FoxO pathway and thus influence early B-cell development [43][44][45][46][47][48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Pierau

Simma

et al. 2012

Eur J Immunol

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Ligation of the BCR induces a complex signaling network that involves activation ofAkt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca 2+ -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-κB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1α was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homozygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function.Keywords: B cell r NFAT r PKB/Akt r SDF1α r STAT5 IntroductionIn the BM B-cell progenitors develop through defined stages of differentiation to immature B cells giving rise to follicular B2 (FO) B cells, marginal zone (MZ), and B1 B cells. These processes are controlled by the signal intensity arising from the pre-BCR or mature BCR, which activate similar sets of signaling molecules. The most proximal signaling events upon BCR ligation include Correspondence: Prof. Ursula H. Bommhardt e-mail: ursula.bommhardt@med.ovgu.de activation of the protein tyrosine kinases Lyn and Syk. A prominent substrate of Syk is the adaptor protein SLP65/BLNK, which recruits Bruton's tyrosine kinase, phospholipase Cγ2, and further signal proteins into supramolecular complexes that trigger the activation of multiple signaling pathways. Activated phospholipase Cγ2 cleaves the membrane lipid phosphatidylinositol-4, 5-bisphosphate (PIP2) to generate diacylglycerol and inositol-1,4,5-trisphosphate (IP3), two second messengers affecting the * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 3381-3393 activation of PKC family members, MAPK activation, and the release of Ca 2+ from intracellular stores, which finally leads to influx of extracellular Ca 2+ . Elevated intracellular Ca 2+ -levels induce the activity of serine/threonine-specific phosphatase calcineurin and, in turn, a set of Ca 2+ -regulated transcription factors, in particular of NFAT and NF-κB factors that control various gene expression programs [1].An important signaling cascade induced after BCR engagement encompasses the lipid kinase family of class I PI3Ks [2][3][4]. Mature peripheral B cells lacking a BCR could be rescued from apoptosis by the ectopic expression of a constitutively active catalytic subunit of PI3K, indicating that PI3K signals support the surv...

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Section: Discussionmentioning

confidence: 99%

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Pierau

Simma

et al. 2012

Eur J Immunol

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“…2,3 These mice have multiple hematopoietic defects, which affect the proliferation and/ or survival of both myeloid and lymphoid lineages, including B-cell development. 4 In the Stat5a/b null/null mice, the precursor B-cell compartment is substantially reduced presumably due to an inability of progenitor B cells to proliferate in response to interleukin-7 (IL-7). However, differentiation towards mature B cells seems to be unaffected.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] Upstream signaling components of the JAK-STAT pathway instead of STAT5 per se are now clearly involved in the mechanisms leading to STAT5 deregulation in leukemic B cells. 4 However, the most direct evidence for STAT5 involvement in cellular proliferation and transformation comes from the analysis of the STAT5 dominant positive mutants that are capable to relieve cell lines from growth factor dependence and can also induce a fatal myeloproliferative disease or a multilineage leukemia in mice. 20,21 Conversely, we have demonstrated that expression of DN-STAT5, in the human 697 leukemic pre-B cell line leads to an increased spontaneous apoptosis that is massively enhanced upon IL-7 stimulation.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Cholez

Debuysscher

Bourgeais³

et al. 2012

Leukemia

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,5,6 STAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6D5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6D5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT-STAT5D5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6D5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis.Leukemia ( INTRODUCTIONThe signal transducer and activator of transcription factors STAT5A and STAT5B are two closely related STAT family members that play a major role in cytokine and growth factor signaling. 1 Number of studies have demonstrated that STAT5 plays a crucial role in hematopoiesis. In particular, the knockout mice models (Stat5a/ b DN/DN and Stat5a/b null/null ) have pointed up the important role of STAT5 in hematopoietic cell development. 2,3 These mice have multiple hematopoietic defects, which affect the proliferation and/ or survival of both myeloid and lymphoid lineages, including B-cell development. 4 In the Stat5a/b null/null mice, the precursor B-cell compartment is substantially reduced presumably due to an inability of progenitor B cells to proliferate in response to interleukin-7 (IL-7). However, differentiation towards mature B cells seems to be unaffected. 5,6 STAT5 is also involved in the regulation of IL-7-dependent germline transcription, histone acetylation and DNA recombination of distal VH gene segments, which are the hallmark of B lymphocyte development. 7 Accordingly, a constitutively active form of STAT5B in IL-7R À / À mice, is sufficient to restore B-cell development. 8 However, the instructive role for STAT5 and IL-7-R signaling in early B-cell development has been controversial in a mouse model of conditional mutagenesis of STAT5. 9 This model showed that the main role of IL-7-mediated activation of STAT5 is to promote pro-B-cell survival via Mcl1 and to prevent premature rearrangements of the immunoglobulin-k light-chain locus (Igk) by binding to the

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“…An important consequence for this translocation is the over-expression of STAT5. STAT5 inactivation results in cell cycle arrest and apoptosis of BCR-ABL pos malignant B cells and BCR-ABL1 pos STAT5 knockout mice do not develop leukemia (Malin et al, 2010). Interestingly, genome-wide analysis of B cell ALL has identified mutations in the STAT5 upstream regulators JAK1 and JAK2 in up to 10% of patients, and patients BCR-ABL pos or with JAK1&2 mutations have a similar gene expression profile and prognosis (Malin et al, 2010).…”

Section: Genes Cytogenetic Alterations and Transcription Factors In mentioning

confidence: 99%

“…STAT5 inactivation results in cell cycle arrest and apoptosis of BCR-ABL pos malignant B cells and BCR-ABL1 pos STAT5 knockout mice do not develop leukemia (Malin et al, 2010). Interestingly, genome-wide analysis of B cell ALL has identified mutations in the STAT5 upstream regulators JAK1 and JAK2 in up to 10% of patients, and patients BCR-ABL pos or with JAK1&2 mutations have a similar gene expression profile and prognosis (Malin et al, 2010). JAK2 mutations lead over-expression of CRLF2 (also known as thymic stromal lymphopoietin receptor) which forms a heterodimeric complex with the IL-7R (Harvey et al, 2010).…”

Section: Genes Cytogenetic Alterations and Transcription Factors In mentioning

confidence: 99%

From HSC to B-Lymphoid Cells in Normal and Malignant Hematopoiesis

Pelayo¹,

Dorantes-Acosta²,

Vadillo³

et al. 2012

Advances in Hematopoietic Stem Cell Research

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STAT5 in B cell development and leukemia

Cited by 71 publications

References 75 publications

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

From HSC to B-Lymphoid Cells in Normal and Malignant Hematopoiesis

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