Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation

Hoelbl, Andrea; Kovacic, Boris; Kerényi, Marc; Simma, Olivia; Warsch, Wolfgang; Cui, Yongzhi; Beug, Hartmut; Hennighausen, Lothar; Moriggl, Richard; Sexl, Veronika

doi:10.1182/blood-2005-09-3596

Cited by 196 publications

(249 citation statements)

References 58 publications

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“…Furthermore, STAT5, which regulates CYCLIN D1 and BCL-xL, is activated by BCR-ABL independent of Jak family proteins (Xie et al, 2001). STAT5a/b-deficient fetal liver hematopoietic progenitors fail to generate leukemia in recipient mice after retroviral transduction with BCR-ABL (Hoelbl et al, 2006). Among these BCR-ABL-related signaling molecules, we previously found that STAP-2 binds to and regulates c-CBL and STAT5 (Sekine et al, , 2009b.…”

Section: Discussionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn up-regulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL-xL and BCL-2. In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Further, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones

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Section: Discussionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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“…Stat5 dominant negative mutants block growth-factor independence and leukemogenic potential of Bcr-Abltransformed myeloid cells (Nieborowska-Skorska et al, 1999). Stat5ab À/À mice die perinatally and liver hematopoietic progenitors from these mice transfected with Bcr-Abl fail to generate leukemia in recipient mice (Hoelbl et al, 2006). RNAi-mediated reduction in Stat5 inhibits Bcr-Abl-dependent proliferation, but not cytokine-dependent proliferation and reduces myeloid colony formation in CML patient samples (Scherr et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Bcr-Abl induces autocrine IGF-1 signaling

et al. 2008

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“…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.…”

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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Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation

Cited by 196 publications

References 58 publications

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

Bcr-Abl induces autocrine IGF-1 signaling

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

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