STAT5 triggers<i>BCR-ABL1</i>mutation by mediating ROS production in chronic myeloid leukaemia

Warsch, Wolfgang; Grundschober, Eva; Berger, Angelika; Gille, Lars; Cerny-Reiterer, Sabine; Tigan, Anca-Sarmiza; Hoelbl-Kovacic, Andrea; Valent, Peter; Moriggl, Richard; Sexl, Veronika

doi:10.18632/oncotarget.806

Cited by 69 publications

(70 citation statements)

References 83 publications

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“…34 A recent publication described a highly significant correlation between the level of STAT5A mRNA and the occurrence of BCR-ABL1 mutations in a cohort of 50 CML patients, possibly mediated by the enforced production of reactive oxygen intermediates. 39 Further support for a link between STAT5 activity and TKI response is provided by a recent phosphoproteinprofiling study that found a significant correlation between the level of phosphorylated STAT5 and the response to TKI treatment. 40 It will be of interest to study whether and how STAT3 induces TKI resistance as STAT3 can compensate for STAT5 under certain circumstances, and there is preliminary evidence to implicate STAT3 in drug resistance in CML.…”

Section: Stat5 In Tki Resistancementioning

confidence: 97%

JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

Warsch

Walz

Sexl

2013

Blood

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The transcription factor signal transducers and activators of transcription 5 (STAT5) has an important and unique role in Breakpoint Cluster Region -Abelson 1 (BCR-ABL1)-driven neoplasias. STAT5 is an essential component in the signaling network that maintains the survival and growth of chronic myeloid leukemia (CML) cells. In contrast, the function of the prototypical upstream kinase of STAT5, the Janus kinase JAK2, in CML is still under debate. Although there is widespread agreement that JAK2 is part of the signaling network downstream of BCR-ABL1, it is unclear whether and under what circumstances JAK2 inhibitors may be beneficial for CML patients. Recent studies in murine models have cast doubt on the importance of JAK2 in CML maintenance. Nevertheless, JAK2 has been proposed to have a central role in the cytokine signaling machinery that allows the survival of CML stem cells in the presence of BCR-ABL1 tyrosine kinase inhibitors. In this review, we summarize the current debate and provide an overview of the arguments on both sides of the fence. We present recent evidence showing that CML stem cells do not depend on BCR-ABL1 kinase activity but require the continuous support of the hematopoietic niche and its distinct cytokine environment and suggest that it has the potential to resolve the dispute.

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Section: Stat5 In Tki Resistancementioning

confidence: 97%

JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

Warsch

Walz

Sexl

2013

Blood

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“…STAT5 regulates the antiapoptotic genes Bcl-xl, Bcl2 , and Mcl1 in various cell types (13)(14)(15)(16)(17). The lack of expression of these genes would explain the almost complete absence of mature NK cells in Stat5 …”

Section: Overexpression Of Bcl2 Rescues Survival Of Stat5-defi Cient mentioning

confidence: 99%

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

et al. 2016

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Natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-defi cient NK cells can be rescued by overexpression of BCL2. Our experiments defi ne STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-defi cient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verifi ed by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These fi ndings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis. SIGNIFICANCE:The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis. Cancer Discov; 6(4); ©2016 AACR . Ni and Cerwenka, p. 347. See related commentary by INTRODUCTIONNatural killer (NK) cells are innate lymphocytes that develop from a common lymphoid progenitor in the bone marrow ( 1 ). They represent the fi rst line of defense against infected, stressed, and malignant cells. Recent evidence has assigned distinct features and functions to tissue-specifi c NK cells ( 2 ). NK cells have organ-specifi c properties, such as distinct profi les of receptor expression or cytokine production ( 3 ). Uterine NK cells secrete high levels of VEGFA and are involved in placental vascularization. The physiologic functions of other organ-specifi c NK-cell subsets are less well understood ( 4 ). STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor PromotionDagmarAll aspects of NK-cell development are regulated by cytokines, their downstream signaling pathways, and transcriptional regulators. These include key cytokines such as IL2, IL12, IL15, IL18, and IL21 ( 5 ), most of which signal via the common γ chain ( 5 ) and activate the JAK-STAT pathway ( 6 ). JAK kinases (JAK1-3 and TYK2) bind to cytokine receptors and are activated by ligand/receptor binding. The activated kinase phosphorylates STAT transcription factors refs. 6,7 ).Consistent with its function as the major STAT protein downstream of IL7, IL2, and IL15, STAT5 is absolutely essential for conventional NK-cell development and survival; Stat5 Δ / Δ Ncr1-iCre Tg mice lack NK cells ( 8 ). It is also important for lymphoid cell development ( 9 ): STAT5 is constitutively active in a plethora of lymphoid malignancies ( 10 ). Recent studies have described somatic Stat5b mutations as active drivers of lymphoid mali...

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“…9 Furthermore, a recent publication described a highly significant correlation between the level of STAT5a mRNA and the occurrence of BCR-ABL1 mutations in a cohort of 50 CML patients, possibly mediated by the enforced production of reactive oxygen intermediates. 96 Moreover, using a mouse model with a conditional null mutation in the Stat5a/b gene locus, Waltz et al have determined the requirement for STAT5 in MPNs induced by BCR-ABL1 in a retroviral transplantation model of CML. 82 They provided evidence that the loss of one Stat5a/b allele results in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients.…”

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confidence: 99%

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

et al. 2014

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417 IntroductionSeveral new targets have recently been identified in neoplastic mast cells (MCs), and various targeted drugs have been examined for their effectiveness in malignant MC disorders. However, most drugs, including new KIT D816V-blocking agents, such as midostaurin (PKC412), 1 and various BCR-ABL1 inhibitors known to block KIT-activity, such as imatinib or dasatinib, 2 have failed to achieve long-lasting remissions in aggressive systemic mastocytosis (ASM). There is a similar problem in Ph + CML, where imatinib-resistant patients do not reach molecular remission even when secondor third-line BCR-ABL1 tyrosine kinase inhibitors (TKIs) are applied, particularly in patients exhibiting the BCR-ABL1 T315I mutant.3 During disease progression, additional signal transduction pathways become activated in neoplastic cells. Among these, AKT and STAT5 are critical downstream signaling molecules constitutively phosphorylated imatinibresistant chronic myeloid leukemia (CML) and KIT D816V + SM. 4,5 This has been demonstrated in vitro using KIT D816V + and BCR-ABL1 + imatinib-resistant cell lines, where inhibition of phosphorylation of these targets has shown their crucial role in cell proliferation. 6,7 It has also been reported that STAT5 and AKT remained activated in neoplastic myeloid cells, even after inhibition of BCR-ABL1 by TKIs. 8 Moreover, during disease progression, the levels of STAT5 mRNA and protein increase, and STAT5 production and activation is triggered not only by BCR-ABL1 or mutant KIT, but also by other pro-oncogenic pathways relevant to disease progression and resistance. 9 Taken together, these observations strongly suggest that STAT5 and AKT are key drivers in drug-resistant CML and SM, and thus represent potential therapeutic targets. Small molecules targeting STAT5 or AKT may indeed be effective in these malignancies, especially in TKIs-resistant patients. However, inhibitors available today, such as pimozide or BP-1-108 for STAT5, 10,11 or perifosine for AKT,12 are neither specific nor potent enough to be applicable in clinical practice. Therefore, it seems important to develop compounds that specifically and potently target STAT5 and AKT. Mast cells and mastocytosis KIT and cytokine signaling in normal mast cellsMCs originate from bone marrow (BM)-derived hematopoietic stem cells (HSCs) that enter the peripheral tissues via the bloodstream and undergo maturation under the Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy open-access paper. doi:10.3324/haematol.2013.098442 Manuscript received on October 8, 2013. Manuscript accepted on December 20, 2013 Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of...

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STAT5 triggersBCR-ABL1mutation by mediating ROS production in chronic myeloid leukaemia

Cited by 69 publications

References 83 publications

JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

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