Stat5 tetramer formation is associated with leukemogenesis

Moriggl, Richard; Sexl, Veronika; Kenner, Lukas; Duntsch, Christopher; Stangl, Katharina; Gingras, Sébastien; Hoffmeyer, Angelika; Bauer, Anna; Piekorz, Roland P.; Wang, Demin; Bunting, Kevin D.; Wagner, Erwin F.; Sonneck, Karoline; Valent, Peter; Ihle, James N.; Beug, Hartmut

doi:10.1016/j.ccr.2004.12.010

Cited by 208 publications

(274 citation statements)

References 41 publications

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“…Here, the leukemogenic potential of a constitutively activated STAT5 molecule was entirely dependent on the ability to form tetramers, as mutants engineered to exclusively form dimers failed to induce leukemia in mice. 39 Because nuclear localization and intranuclear mobility of the dimeric RUNX1/ETO were not altered compared with the tetrameric counterpart (data not shown), the lack of leukemogenic properties of RUNX1/ETO dimers may result from impaired binding to cofactors or to a defect in DNA-binding activity essential for cellular transformation. RUNX1/ETO tetramers are known to associate with a wide variety of factors, including the ETO family members ETO, MTG16, and MTGR1 and with proteins involved in induction of repressive chromatin, although their contribution to the leukemogenic potential of RUNX1/ETO is still not clear.…”

Section: Discussionmentioning

confidence: 94%

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

Wichmann

Becker

Chen-Wichmann

et al. 2010

Blood

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RUNX1/ETO, the fusion protein resulting from the chromosomal translocation t(8;21), is one of the most frequent translocation products in acute myeloid leukemia. Several in vitro and in vivo studies have shown that the homo-tetramerization domain of ETO, the nervy homology region 2 (NHR2), is essential for RUNX1/ETO oncogenic activity. We analyzed the energetic contribution of individual amino acids within the NHR2 to RUNX1/ETO dimertetramer transition and found a clustered area of 5 distinct amino acids with strong contribution to the stability of tetramers. Substitution of these amino acids abolishes tetramer formation without affecting dimer formation. Similar to RUNX1/ ETO monomers, dimers failed to bind efficiently to DNA and to alter expression of RUNX1-dependent genes. RUNX1/ETO dimers do not block myeloid differentiation, are unable to enhance the selfrenewal capacity of hematopoietic progenitors, and fail to induce leukemia in a murine transplantation model. Our data reveal the existence of an essential structural motif (hot spot) at the NHR2 dimertetramer interface, suitable for a molecular intervention in t(8;21) leukemias. IntroductionChromosomal translocations are frequent events during malignant cell transformation, particularly during leukemogenesis. 1 The translocation t(8;21), one of the most frequent chromosomal anomalies in acute myeloid leukemia (AML), involves the RUNX1 gene (also known as AML1, CBF␣2, or PEBP2␣B) on chromosome 21 and the ETO gene (also known as MTG8 or RUNX1T1) on chromosome 8. The ubiquitously expressed RUNX1 is a transcription factor and belongs to the key regulators of hematopoietic cell differentiation. 2 The fusion protein RUNX1/ETO contains the DNA-binding domain (Runt, RHD) of the RUNX1 transcription factor but lacks the C-terminal transactivation sequence that is replaced by almost the entire ETO protein. 2 forms of RUNX1/ETO coexist in AML-leukemia samples: the originally discovered full-length RUNX1/ETO and a splice variant called RUNX1/ETO9a, which lacks 178 amino acids at the C-terminus. Only RUNX1/ETO9a does not require cooperative events for inducing leukemia development in mice. 3,4 We and others have shown that RUNX1/ETO has a modular structure. Besides the Runt domain, RUNX1/ETO contains 4 functional domains, which are generally referred to as nervy homology region (NHR1 to NHR4). The NHR domains serve as docking interface for a variety of different proteins, including the E-protein HEB, 5,6 the apoptosis-related protein SON, 7 and nuclear corepressor proteins, such as N-CoR, SMRT, mSIN3A, and MTGR1, as well as histone deacetylases (HDACs). [8][9][10][11] In addition, the NHR2 domain mediates tetramer formation through hydrophobic and ionic/polar interactions. Two ␣-helices align in a head-to-tail fashion to form an antiparallel dimer. Two dimers subsequently are positioned on top of each other in a sandwich-like fashion. The total interaction area composing all contact points of the 4 ␣-helices is approximately 10 000 Å. 2 Substitution of 7 leucines withi...

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Section: Discussionmentioning

confidence: 94%

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

Wichmann

Becker

Chen-Wichmann

et al. 2010

Blood

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“…The N-terminal region of STAT5 has been implicated in both positive and negative regulatory functions of nuclear STAT5, including nuclear retention, protein dephosphorylation, oligomerization, and co-factor recruitment 48 . Among these properties, STAT5 tetramerization has emerged as a central feature of optimal STAT5 activity, especially critical for stimulating the expression of genes with suboptimal STAT5 consensus binding motifs 49 . The underlying basis for the relatively normal IL-7-regulated adult intrathymic T cell development mediated by N-terminal truncated STAT5 protein versus aberrant development of lymphoid lineages controlled by IL-15 in FlStat5 -/-mice is likely to entail cell-type specific differences in both the quantitative and qualitative aspects of IL-7 and IL-15-mediated signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

2005

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AbstractγδT cells are prevalent in the mucosal epithelia and are postulated to act as sentries to maintain tissue integrity. What these γδT cells recognize is poorly defined, but based on the restricted T cell receptor (TCR) repertoire, the notion that they are selected by self-antigens of low complexity has been widely disseminated. We present data demonstrating that generation of the restricted TCR Vγ gene repertoire of intestinal intraepithelial lymphocytes is regulated by IL-15, which induces Vγ gene segmentspecific local chromatin modifications and enhanced accessibility conducive for subsequent targeted gene rearrangement. This cytokine-directed tissue-specific TCR repertoire formation likely reflects distinct TCR repertoire selection criteria for γδ and αβT cell lineages adopted for different antigen recognition strategies.Intestinal intraepithelial lymphocytes (i-IELs) found within the intestinal epithelial layer are an essential component of mucosal immunity. Similar to T cell subsets in other lymphoid tissues, i-IELs are composed of two T cell types, αβ and γδT cells. In contrast to other tissues, however, γδT cells are prevalent in the mucosal epithelia of most vertebrates and are thought to be a major source of secreted factors necessary for the maintenance of tissue integrity subsequent to infection, transformation, or cell injury 1-3 .Despite the long history of i-IELs, their origin and ligand specificity remain uncertain. Earlier work has indicated that αβ i-IELs originate exclusively from the thymus in normal mice 4 , but whether γδ i-IELs are subject to similar developmental constraints is unclear. The majority of human and mouse γδ i-IELs express the homodimeric αα form of the CD8 coreceptor and exhibit restricted Variable (V) γ and V δ gene usage. In C57BL/6 (B6) mice, for example, V γ 5 expressing cells constitute the predominant i-IEL population in the small intestine [5][6][7] . Mouse strain-specific preferential usage of Tcrg and Tcrd genes among i-IELs arises from complex molecular and cellular controls with evidence for genetic linkage to the Tcrg, Tcrd and H2 loci 6,8,9 , but the exact mechanism is unknown. Two non-mutually exclusive mechanistic processes can be considered to account for the restricted TCR gene usage: cellular selection and programmed TCR gene rearrangement. A hallmark of adaptive immunity is the cellular selection process geared toward forming a population of cells with antigen receptor repertoires that can recognize the entire external universe of antigens. This selection pressure acts on immature cell subsets expressing randomly generated clonal antigen receptors. Although the TCR-driven selection shaping the αβTCR repertoire of conventional αβT cells constitutes a fundamental theme in immunology, whether a similar process is needed for γδT cell development, and specifically for γδ i-IELs, remains a matter of debate [10][11][12] .

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“…Furthermore, constitutive activation of Stat5 up-regulates the expression of genes, including Bcl-x, Mcl-1, and cyclin D1/2, which are associated with survival and proliferation in chronic myelogenous leukemia (CML) cells (11 -14). Taken together, increasing evidence indicates that persistent activation of Stat5 and consequent deregulation of downstream gene expression contribute to malignant progression in CML (1,7,15).…”

Section: Introductionmentioning

confidence: 92%

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Nam¹,

Williams

Vultur³

et al. 2007

Molecular Cancer Therapeutics

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Dasatinib (BMS-354825) is a novel, oral, potent, multitargeted kinase inhibitor of Bcr-Abl and Src family kinases (SFK) and is a promising cancer therapeutic agent. Preclinical data indicate that dasatinib is 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl, and that dasatinib is active against 18 of 19 Bcr-Abl mutations known to cause imatinib resistance. Phase I clinical data show that dasatinib is well tolerated and highly effective for the treatment of imatinib-resistant/ imatinib-intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome -positive acute lymphoblastic leukemia. However, the molecular mechanism of action of dasatinib is not fully understood. In this study, we confirm that dasatinib inhibits tyrosine phosphorylation of SFKs, including Src, Hck, and Lyn, in K562 human CML cells. Significantly, downstream signal transducer and activator of transcription 5 (Stat5) signaling is also blocked by dasatinib as shown by decreases in levels of phosphorylated Stat5 and Stat5 DNA-binding activities. In addition, dasatinib down-regulates expression of Stat5 target genes, including Bcl-x, Mcl-1, and cyclin D1. Consistent with these results, blockade of Stat5 signaling by dasatinib is accompanied by inhibition of cell proliferation and induction of apoptosis. Surprisingly, Stat5 DNA-binding activities are enhanced with increasing cell density, which is associated with resistance to apoptosis by dasatinib. Our findings indicate that inhibition of Stat5 signaling downstream of Bcr-Abl/SFKs contributes to the action of dasatinib, and, conversely, that increasing cell density up-regulates Stat5 activation and confers resistance to dasatinib. Moreover, the level of phosphorylated Stat5 in CML cells represents a mechanistically relevant biomarker for monitoring inhibition of Bcr-Abl signaling by dasatinib in CML patients using convenient immunocytochemical assays.

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Stat5 tetramer formation is associated with leukemogenesis

Cited by 208 publications

References 41 publications

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

Interleukin 15 controls the generation of the restricted T cell receptor repertoire of γδ intestinal intraepithelial lymphocytes

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

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