BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia

Hantschel, Oliver; Warsch, Wolfgang; Eckelhart, Eva; Kaupe, Ines; Grebien, Florian; Wagner, Kay Uwe; Superti‐Furga, Giulio; Sexl, Veronika

doi:10.1038/nchembio.775

Cited by 163 publications

(175 citation statements)

References 49 publications

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“…AG490 generally tends to induce dose-dependent reduction of proliferation and induction of apoptosis, in concentrations where STAT activation was not prevented. 55 Moreover, recent studies have also highlighted the low potency of AG490 for inhibition of Jak2 56 or even the total lack of Jak2-inhibition 57 at concentrations of 5 mM. Our data indicate that Jaks are no suitable drug targets in F/PDGFRa-positive cells and that it is questionable whether patients would benefit from treatment with Jak inhibitors.…”

Section: Discussioncontrasting

confidence: 37%

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

et al. 2015

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ABSTRACT. Aberrant activation of oncogenic kinases is frequently observed in human cancers, but the underlying mechanism and resulting effects on global signaling are incompletely understood. Here, we demonstrate that the oncogenic FIP1L1-PDGFRa kinase exhibits a significantly different signaling pattern compared to its PDGFRa wild type counterpart. Interestingly, the activation of primarily membrane-based signal transduction processes (such as PI3-kinase-and MAP-kinase-pathways) is remarkably shifted toward a prominent activation of STAT factors. This diverging signaling pattern compared to classical PDGF-receptor signaling is partially coupled to the aberrant cytoplasmic localization of the oncogene, since membrane targeting of FIP1L1-PDGFRa restores activation of MAPK-and PI3K-pathways. In stark contrast to the classical cytokine-induced STAT activation process, STAT activation by FIP1L1-PDGFRa does neither require Janus kinase activity nor Src kinase activity. Furthermore, we investigated the mechanism of STAT5 activation via FIP1L1-PDGFRa in more detail and found that STAT5 activation does not involve an SH2-domain-mediated binding mechanism. We thus demonstrate that STAT5 activation occurs via a non-canonical activation mechanism in which STAT5 may be subject to a direct phosphorylation by FIP1L1-PDGFRa.

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Section: Discussioncontrasting

confidence: 37%

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

et al. 2015

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“…Constitutive activation of STAT5 has been demonstrated as a mechanism for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL fusion (21). We found that DNA binding activity of STAT5 is suppressed when BCR-ABL is inactivated by imatinib.…”

Section: Analysis Of Dynamic Changes Of Global Tf-dna Binding Patternmentioning

confidence: 64%

Proteome-wide profiling of activated transcription factors with a concatenated tandem array of transcription factor response elements

Chen

Chan

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

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Transcription factors (TFs) are families of proteins that bind to specific DNA sequences, or TF response elements (TFREs), and function as regulators of many cellular processes. Because of the low abundance of TFs, direct quantitative measurement of TFs on a proteome scale remains a challenge. In this study, we report the development of an affinity reagent that permits identification of endogenous TFs at the proteome scale. The affinity reagent is composed of a synthetic DNA containing a concatenated tandem array of the consensus TFREs (catTFRE) for the majority of TF families. By using catTFRE to enrich TFs from cells, we were able to identify as many as 400 TFs from a single cell line and a total of 878 TFs from 11 cell types, covering more than 50% of the gene products that code for the DNA-binding TFs in the genome. We further demonstrated that catTFRE pull-downs could quantitatively measure proteome-wide changes in DNA binding activity of TFs in response to exogenous stimulation by using a labelfree MS-based quantification approach. Applying catTFRE on the evaluation of drug effects, we described a panoramic view of TF activations and provided candidates for the elucidation of molecular mechanisms of drug actions. We anticipate that the catTFRE affinity strategy will find widespread applications in biomedical research.TF activity profiling | transcriptional coregulator | drug effects screening A lmost all biological processes, ranging from cell cycle regulation to organ development, are controlled by the transcriptional regulatory system (1). In the classic cell membraneto-nucleus signal transduction paradigm, transcription factors (TFs) are the final effectors. They are activated and bind to consensus DNA sequences to execute specific transcriptional programs in response to the signal. Thus, the ability to monitor TF activity is important for the delineation of signal transduction pathways when the cells are perturbed (e.g., treated with a drug), or when organs are under the influence of developmental cues.Approximately 1,500 TF coding genes are reported to be in the human genome (2). TFs can be grouped into different families depending on the structure of their DNA binding domains. There are approximately 50 TF families (2), and each family prefers to bind a specific DNA consensus sequence. For example, nuclear receptors (NRs) are ligand-modulated TFs that recognize one or two hormone response element sequences such as 5′-AGAACA-3′ or 5′-AGGTCA-3′ (3). Previous studies have demonstrated the importance of linking an extracellular signaling event to the activation of TFs. For example, assigning Forkhead box (Fox) P3 to a signaling module that is crucial for regulatory T-cell development has accelerated our understanding of signal transductions and gene functions (4).The abundance of TFs in the cells is currently inferred from mRNA profiling. Yang et al. identified 45 of 49 known NRs from several tissues in mice and linked NR expression to the circadian clock (5). Bookout et al. surveyed the expression of al...

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“…18 Several groups have recently demonstrated the successful targeting of both BCR-ABL-1 and JAK2 in the CML stem cells in in vitro models of CML stem cells procured from imatinib-resistant patients. 19 The notion of combining ABL-1 TKIs and JAK inhibitors, however, remains uncertain at this time. 20 Other candidate pharmacological interventions of interest include innovative methods in targeting the bone marrow microenvironment which can function as a protective factor against TKI-induced apoptosis of CML stem cells and several diverse strategies, including the combination of TKIs with other candidate inhibitors which target diverse signaling pathways, including WNT/β-catenin, Hedgehog, TGF-β/FoxO3a/BCL6 and JAK2/PP2A.…”

Section: Stem Cells and Efforts To Target Themmentioning

confidence: 99%

Current pre-clinical and clinical advances in the BCR-ABL1-positive and -negative chronic myeloproliferative neoplasms

et al. 2014

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BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia

Cited by 163 publications

References 49 publications

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

Proteome-wide profiling of activated transcription factors with a concatenated tandem array of transcription factor response elements

Current pre-clinical and clinical advances in the BCR-ABL1-positive and -negative chronic myeloproliferative neoplasms

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