Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells

Bar-Natan, Michal; Nelson, Erik A.; Walker, Sarah R.; Kuang, Yanan; Distel, R; Frank, David A.

doi:10.1038/leu.2011.338

Cited by 38 publications

(45 citation statements)

References 13 publications

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“…Therefore, in this setting, STAT5 inhibitors may not be a useful therapy, since genes that are normally repressed by STAT5, including BCL6, would be upregulated by STAT3, promoting a potentially more aggressive tumor. Both STAT3 and STAT5 can also be activated in leukemias (32,33), and these STATs have similar opposite effects on the regulation of BCL6 expression in hematopoietic cells (data not shown), though the relative contributions of STAT5 and STAT3 to the biology of these cells are unclear. Understanding the patterns of activation of these STATs in malignant cells, and their effects alone and in combination on gene expression, may have important implications for targeted cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

Walker

Nelson

Yeh

et al. 2013

Molecular and Cellular Biology

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Inappropriate activation of the transcription factors STAT3 and STAT5 has been shown to drive cancer pathogenesis through dysregulation of genes involved in cell survival, growth, and differentiation. Although STAT3 and STAT5 are structurally related, they can have opposite effects on key genes, including BCL6. BCL6, a transcriptional repressor, has been shown to be oncogenic in diffuse large B cell lymphoma. BCL6 also plays an important role in breast cancer pathogenesis, a disease in which STAT3 and STAT5 can be activated individually or concomitantly. To determine the mechanism by which these oncogenic transcription factors regulate BCL6 transcription, we analyzed their effects at the levels of chromatin and gene expression. We found that STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. STAT5, in contrast, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene. Furthermore, the repression mediated by STAT5 is dominant over STAT3-mediated induction. STAT5 exerts this effect by displacing STAT3 from one of the two regulatory regions to which it binds. These findings may underlie the divergent biology of breast cancers containing activated STAT3 alone or in conjunction with activated STAT5.

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Section: Discussionmentioning

confidence: 99%

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

Walker

Nelson

Yeh

et al. 2013

Molecular and Cellular Biology

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“…drugs that could be used in proof-of-concept clinical trials, they used a chemical library that contained compounds known to be safe in humans. [9][10][11] These studies have led to identify the neuroleptic drug pimozide (1, Fig. 1) as potent STAT5 inhibitor and potent inductor of apoptosis in CML cells.…”

Section: Introductionmentioning

confidence: 99%

“…Reported results are just excluding a direct inhibition of different STAT5 activator kinases, such as FLT3 ITD transformed in AML, mutated BCR/ABL in CML, and various JAK subtypes. [9][10][11] The particular structure-activity relationship of compounds 20-23 suggests a finely tuned interaction with the biological counterpart(s). Finally, simple alkyl, N-methyl (4) or -benzyl (5), appendages were found of no interest.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

Rondanin

Daniele

Romagnoli

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tSTATs are transcription factors acting as intracellular signaling after stimulation with cytokines, growth factors and hormones. STAT5 is also constitutively active in many forms of cancers, including chronic myelogenous leukemia, acute lymphoblastic leukemia and Hodgkin's lymphoma. Recently, literature reported that the neuroleptic drug pimozide inhibits STAT5 phosphorylation inducing apoptosis in CML cells. We undertook an investigation from pimozide structure, obtaining simple derivatives with cytotoxic and STAT5-inhibitory activity, two of them markedly more potent than pimozide.Ó 2014 Elsevier Ltd. All rights reserved.Signal transducers and activators of transcription (STATs) are transcription factors that act as intracellular signaling after stimulation with cytokines, growth factors and hormones. STATs are activated into the cytosol by phosphorylation of specific tyrosine residues forming homo-or heterodimers that enter into the nucleus and bind to the specific DNA sequences in the promoter regions of various genes involved in cell survival, proliferation and differentiation. 1 STAT5 protein consists of a N-terminal domain that is involved in promoting STAT5 dimerization, a DNA binding domain that interacts with a conserved DNA binding sequence, an SH2 domain that drives the initial interaction of STAT5 protein with phosphorylated tyrosine residues in the cytoplasmic tails of cytokine receptors, and a C-terminal transactivation domain. 2 In order to be functional, STAT5 proteins must first be activated. This activation is carried out by kinases associated with transmembrane receptors. Firstly, ligands (cytokines, growth factors) binding to these transmembrane receptors on the outside of the cell activate JAK2 (Janus kinase 2) which in turn add a phosphate group to a specific tyrosine residue on the receptor; STAT5 then binds to these phosphorylated-tyrosines using their SH2 domain. The bound STAT5 is then phosphorylated by JAK2 and the phosphorylated STAT5 finally goes on to form either homodimers, STAT5-STAT5, or heterodimers, STAT5-STATX, with other STAT proteins. 3,4 The interest of STAT5 in oncology comes from the initial observations of its activation in many malignancies. Epigenetic changes, regulation by miRNA, altered proteolytic pathways, gene amplification and aberrant growth factor signaling contribute to activation of STAT5 proteins in human cancers; however, mutations in STAT5 genes have not been found, with the exception of myeloid leukemia, where the STAT5 C-terminal part fuses with RARa. In contrast, mutations in signaling pathways acting upstream of STAT5 proteins are frequent in many cancer types.Constitutively STAT5 activation was found in hematological malignancies such as acute lymphocytic leukemia (ALL), erythroleukemia, chronic myelogenous leukemia (CML) and in others myeloproliferative diseases. 5 Differently from normal cells in which STAT5 is activated by JAK2, in ALL and CML the products of the fusion proteins TEL/ JAK2 and BCR/ABL activate directly STAT5 proteins...

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“…Targeting other components of the JAK/STAT pathway makes sense given that this pathway is an essential mediator of almost all forms of Philadelphiachromosome-negative MPNs. Several preclinical and early-stage studies are focused on combining targeting therapies against both BCL-XL and JAK2 (12,13), STAT5 and JAK2 (14,15), or the cell cycle-related proteins CDC25 and PIM1 (46,47). To date, there is no evidence that inhibiting these targets enhances survival or prehematocrit were not significantly reduced.…”

Section: Plek2mentioning

confidence: 99%

“…A BclxL inhibitor was also combined with interferon α to specifically target JAK2 V617F -positive hematopoietic progenitor cells (13). Furthermore, pimozide, a STAT5 inhibitor, was reported to be effective in cell lines or primary cells by itself or in combination with a JAK2 inhibitor (14,15).…”

Section: V617fmentioning

confidence: 99%

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

Zhao¹,

Mei²,

Cao³

et al. 2017

Journal of Clinical Investigation

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Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells

Cited by 38 publications

References 13 publications

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6

Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

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