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

Joliot, Véronique; Cormier, Françoise; Medyouf, Hind; Alcalde, Hélène; Ghysdael, Jacques

doi:10.1038/sj.onc.1209480

Cited by 31 publications

(33 citation statements)

References 54 publications

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“…4,6,13 A flow cytometrybased characterization of the baseline activation status of several STAT proteins in malignant CD19…”

Section: Constitutive Activation Of Stat5 In Wmmentioning

confidence: 99%

“…[4][5][6][7][8] Despite a high degree of amino acid sequence homology, STAT5A and STAT5B are distinct transcription factors, with evidence indicating both overlapping and nonredundant functional activities for these isoforms in solid tumors.…”

Section: Introductionmentioning

confidence: 99%

“…3 Hyperactivation of these proteins, either in response to heightened cytokine signaling or secondary to activating mutations within the JAK/STAT pathway, leads to carcinogenesis, with numerous reports suggesting an association between constitutive STAT5 activation and uncontrolled cellular proliferation in hematologic malignancies. [4][5][6][7][8] Despite a high degree of amino acid sequence homology, STAT5A and STAT5B are distinct transcription factors, with evidence indicating both overlapping and nonredundant functional activities for these isoforms in solid tumors. [9][10][11][12] However, the activation and downstream function of the STAT5 isoforms in lymphoma have not been well characterized.…”

Section: Introductionmentioning

confidence: 99%

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Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenström's macroglobulinemia

Hodge

Ziesmer

Yang

et al. 2014

Blood

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Key Points• STAT5 is constitutively phosphorylated in malignant B cells obtained from patients with Waldenström's macroglobulinemia.• Inhibition of STAT5 signaling significantly decreases IgM production and may be useful therapeutically for patients with high IgM levels.Activation of the Janus kinase family/signal transducer and activator of transcription (JAK/STAT) signaling pathway has been associated with the pathogenesis and progression of both solid and hematologic malignancies. We have detected constitutive activation of STAT5 in malignant B cells derived from patients with Waldenström's macroglobulinemia (WM). Although short hairpin RNA-mediated knockdown of the STAT5A and STAT5B isoforms did not affect cellular proliferation, loss of STAT5 significantly decreased immunoglobulin M (IgM) secretion. A similar dose-dependent inhibition of IgM secretion was observed when WM cell lines were treated with a small molecule inhibitor of STAT5. These data suggest that STAT5 is involved in regulating IgM production in WM and that inhibition of STAT5 may represent a novel therapeutic strategy for lowering IgM levels in WM patients. (Blood. 2014;123(7):1055-1058) IntroductionSignaling events initiated by cytokines within the bone marrow microenvironment are necessary for the viability and development of normal B cells. Such events are equally important for the maintenance of many B-cell malignancies as well, including Waldenström's macroglobulinemia (WM), a lymphoplasmacytic lymphoma characterized by high levels of serum immunoglobulin M (IgM). 1,2 One of the most prominent signaling cascades activated by cytokines is the Janus kinase family/signal transducers and activators of transcription (JAK/STAT) pathway composed of 4 JAK proteins (JAK1-JAK3, Tyk2) and 7 STAT proteins (STAT1-STAT6, including STAT5A and STAT5B).3 Hyperactivation of these proteins, either in response to heightened cytokine signaling or secondary to activating mutations within the JAK/STAT pathway, leads to carcinogenesis, with numerous reports suggesting an association between constitutive STAT5 activation and uncontrolled cellular proliferation in hematologic malignancies. [4][5][6][7][8] Despite a high degree of amino acid sequence homology, STAT5A and STAT5B are distinct transcription factors, with evidence indicating both overlapping and nonredundant functional activities for these isoforms in solid tumors.9-12 However, the activation and downstream function of the STAT5 isoforms in lymphoma have not been well characterized. Here, we have explored the relationship between STAT5 phosphorylation and the biologic activity of WM tumor cells. Our data indicate that STAT5 is hyperactive in malignant WM B cells and promotes IgM secretion, and that investigations into the targeting of both STAT5A and STAT5B clinically are warranted. Methods Cell lines and reagentsThe WM cell lines, MWCL-1, BCWM.1, and RPCI-WM1, were cultured as described.2 CD19 1 CD1381 WM cells were isolated from the bone marrows of consenting patients, using positive selection beads...

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“…4,6,13 A flow cytometrybased characterization of the baseline activation status of several STAT proteins in malignant CD19…”

Section: Constitutive Activation Of Stat5 In Wmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenström's macroglobulinemia

Hodge

Ziesmer

Yang

et al. 2014

Blood

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“…STAT5 overexpression or activation in transgenic T cells leads to an increase in CD8 ϩ T-cell numbers. [42][43][44] Conversely, mice deficient in both Stat5a and Stat5b present a severe reduction in CD8 ϩ T cells. 45,46 Recently, it has been reported that IL-2 receptor/ STAT5 signaling contributes to establish a CD8 effector differentiation program following low-avidity TCR stimulation.…”

mentioning

confidence: 99%

Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

Santos

Rickman

Reyniès

et al. 2006

Blood

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The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from ESR␣-TEL-JAK2 transgenic mice present an aberrant CD8 ؉ differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4 ؊ CD8 ؊ double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3⑀-and pT␣-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCR␣␤ transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCR␣␤ expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs. IntroductionIn the thymus, T cells develop from a common CD4 Ϫ CD8 Ϫ double-negative (DN) progenitor into 2 main lineages, ␣␤ and ␥␦, which are defined by the selection of productive rearrangements in the respective T-cell receptor (TCR) loci (for a review, see Aifantis et al 1 ). In mice, DN thymocytes are divided in 4 categories according to CD25 and CD44 expression: DN1 (CD25 Ϫ CD44 ϩ ), DN2 (CD25 ϩ CD44 ϩ ), DN3 (CD25 ϩ CD44 Ϫ ), and DN4 (CD25 Ϫ CD44 Ϫ ). Rag-mediated rearrangement of the TCR␤ locus at the DN3 stage leads to cell surface expression of a functional TCR␤ chain, which assembles with the surrogate pT␣ chain and CD3-signaling proteins to form the pre-TCR complex. Constitutive survival, proliferation, and differentiation signals emanating from the pre-TCR allow T cells to pass through the ␤-selection checkpoint and mature to the DN4, CD4 Ϫ CD8 ϩ immature single-positive (ISP) and CD4 ϩ CD8 ϩ double-positive (DP) stages. The ␤-selected cells rearrange their TCR␣ locus, and only the minority of cells expressing a functional TCR␣␤ complex at the cell surface will either undergo negative selection and die or undergo positive selection and become mature CD4 or CD8 single-positive (SP) thymocytes.Chromosomal rearrangements or point mutations in oncogenes or tumor suppressor genes occur in hematopoietic stem cells (HSCs), uncommitted and committed lymphoid progenitors, or developing thymocytes, thus leading to T-cell leukemia. Chromosomal translocations involving the juxtaposition of protooncogenes to the promoter and enhancer sequences of TCR loci result in deregulated oncogene expression. Chromosomal translocations can also create fusion genes encoding fu...

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“…The transcriptional targets of STAT proteins play roles in cell cycle progression as well as cell survival. Constitutively active STATs, particularly STAT3 and STAT5, often contribute to the malignant phenotype in diverse tumor types, including lymphomas (21,22,(32)(33)(34)(35). However, in certain situations, STAT5 is associated with favorable outcome (22,36) and can act as a tumor suppressor and inhibitor of metastasis (37,38).…”

Section: Discussionmentioning

confidence: 99%

Signal Transducers and Activators of Transcription 5a–Dependent Cross-talk between Follicular Lymphoma Cells and Tumor Microenvironment Characterizes a Group of Patients with Improved Outcome after R-CHOP

Taskinen

Valo²,

Karjalainen–Lindsberg³

et al. 2010

Clinical Cancer Research

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Purpose: Tumor microenvironment has a strong effect on the survival of follicular lymphoma (FL) patients. The aim of this study was to determine what are the signaling pathways that mediate the cross-talk between lymphoma cells and tumor-infiltrating inflammatory cells and contribute to the clinical outcome of FL patients. Experimental Design: Gene expression profiling and pathway impact analyses were done from pretreatment lymphoma tissue of 24 patients. The findings were validated immunohistochemically in an independent cohort of 81 patients. All patients were treated with the combination of rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone chemotherapy. In addition, microarray was used to screen the genes differentially expressed between control and rituximab-stimulated B-cell lymphoma cells in culture. Results: Among the transcripts differentially expressed in the FL tissues between the patients with favorable or adverse outcomes, an overrepresentation of genes associated with the signal transducers and activators of transcription (STAT)5a pathway was observed. In a validation set, a better progression-free survival was observed among the patients with high STAT5a protein expression. In the FL tissue, STAT5a positivity was barely detectable in the neoplastic B cells, but a subpopulation of follicular dendritic cells and T lymphocytes showed prominent STAT5a expression. Rituximab was found to induce the expression of STAT5a-associated interleukin-15 in B-lymphoma cells in culture, thereby providing a possible explanation for the cross-talk between rituximab-stimulated FL cells and their microenvironment. Conclusion: The findings suggest that STAT5a activity in immunologically active nonmalignant cells acts as molecular predictor for rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone–treated FL patients. Clin Cancer Res; 16(9); 2615–23. ©2010 AACR.

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

Cited by 31 publications

References 54 publications

Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenström's macroglobulinemia

Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenström's macroglobulinemia

Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

Signal Transducers and Activators of Transcription 5a–Dependent Cross-talk between Follicular Lymphoma Cells and Tumor Microenvironment Characterizes a Group of Patients with Improved Outcome after R-CHOP

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