The role of the STAT5 proteins in the proliferation and apoptosis of the CML and AML cells

Baśkiewicz-Masiuk, Magdalena; Machaliński, Bogusław

doi:10.1111/j.1600-0609.2004.00242.x

Cited by 40 publications

(25 citation statements)

References 41 publications

(61 reference statements)

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“…38 Interestingly, we consistently observe a decrease of one of the STAT5 isoforms recognized by this STAT5 antibody with CC mut3 treatment (Figure 2A, lane 4, top p-STAT5 band disappears, presumably STAT5a), while a decrease in the lower STAT5 band is seen with ponatinib treatment (Figure 2A, lane 2, bottom p-STAT5 band reduced, presumably STAT5b). 39–41 In future studies, it would be intriguing to explore other differential pathways that are differentially regulated by CC mut3 vs. ponatinib.…”

Section: Discussionmentioning

confidence: 99%

Multidomain Targeting of Bcr-Abl by Disruption of Oligomerization and Tyrosine Kinase Inhibition: Toward Eradication of CML

Miller¹,

Woessner²,

Sirch³

et al. 2013

Mol. Pharmaceutics

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The oncoprotein Bcr-Abl, the causative agent of chronic myeloid leukemia (CML), requires homo-oligomerization via a coiled-coil domain to function.1–4 While tyrosine kinase inhibitors (TKIs) have shown great efficacy as treatment options for CML, their use may cause an acquisition of mutations in the tyrosine kinase domain which prevent TKI binding and lead to a loss in activity.5 Previously, we have shown that a rationally modified coiled-coil domain (CCmut3) can disrupt this oligomerization, inhibit proliferation, and induce apoptosis in CML cells.6 Here, we show that using the most recently approved TKI, ponatinib (Iclusig™), in combination with CCmut3 allows a dose reduction of ponatinib and increased therapeutic efficacy in vitro measured by reduction in kinase activity, induction of apoptosis via caspase-3/7 and 7AAD/Annexin V assays, and reduced transformative ability measured by a colony forming assay. The combination was effective not only in cells containing wild-type Bcr-Abl (K562, Ba/F3-p210) but also cells with Bcr-Abl containing the T315I mutation (Ba/F3-p210-T315I). In addition, we report for the first time the ability of CCmut3 alone to inhibit the T315I mutant form of Bcr-Abl. This novel combination may prove to be more potent than single agent therapies and should be further explored for clinical use.

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Section: Discussionmentioning

confidence: 99%

Multidomain Targeting of Bcr-Abl by Disruption of Oligomerization and Tyrosine Kinase Inhibition: Toward Eradication of CML

Miller¹,

Woessner²,

Sirch³

et al. 2013

Mol. Pharmaceutics

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“…The RNA pellets obtained were resolved in 27 ll of DEPC-treated water and added to 2 ll Oligo(dT) [12][13][14][15][16][17][18] primer (Invitrogen, Carlsbad, CA) and 2 ll of 10 mM dNTP mix (Takara Bio Inc., Kyoto, Japan). After incubation at 708C for 5 min, the sample mixture was supplemented with 4 ll of 103 RT reaction buffer, 4 ll dithiothreitol (DTT), 0.5 ll ReverScript II (Wako), and 0.5 ll RNasin ribonuclease inhibitor (Promega, Madison, WI), and incubated at 428C for 90 min, followed by incubation at 758C for 15 min.…”

Section: Reverse Transcription (Rt)-pcrmentioning

confidence: 99%

“…Mammalian STAT5 consists of two highly related homologs, STAT5A and B [7], which form a homodimer or heterodimer [8] to coregulate cell growth and differentiation in various cell types [9][10][11][12][13]. Stat5a À/À /Stat5b À/À double-knockout mice exhibit female infertility [14].…”

Section: Introductionmentioning

confidence: 99%

Involvement of the STAT5 Signaling Pathway in the Regulation of Mouse Preimplantation Development

Nakasato

Shirakura

Ooga

et al. 2006

Biology of Reproduction

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The signal transducer and activator of transcription 5 (STAT5) is an essential factor in the signal transduction pathways for a number of cytokines that regulate the growth and differentiation of mammalian cells. In this study, we investigated the STAT5 signaling pathway in mouse embryos, to elucidate the mechanism of cytokine signal transduction that regulates preimplantation development. The results of the RT-PCR analysis showed that both STAT5A and B were expressed throughout preimplantation development. Immunocytochemistry revealed that the STAT5A/B proteins were located in the nucleus from the early 1-cell stage to the blastocyst stage. STAT5 activation appeared to be regulated by Janus kinases (JAKs) and SRC family kinases (SFKs), since inhibitors of these kinases inhibited the localization of STAT5 proteins to the nucleus. The JAK inhibitor Ag490 reduced both the developmental rate of the embryos and the expression levels of the downstream genes of the JAK-STAT5 signaling pathway. These findings suggest that STAT5 proteins function in preimplantation development by mediating the signals from cytokines.

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“…STAT5 activation is correlated with functional effects on cell cycle progression and resistance to apoptosis through increased expression of cyclin D1 and Bcl-xl, respectively [11,12] and is essential for leukemic cell survival [13,15]. Moreover, many studies have shown that the constitutive STAT5 activation induced by the BCR–ABL oncogene plays an important role in the pathogenesis of CML [11–13], as shown by evidence that murine STAT5-null bone marrow cells were inefficient in generating and maintaining a CML-like disease [16].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the mechanism through which BCR–ABL contributes to malignant transformation is dependent from the ability of this oncoprotein to activate a variety of signaling pathways and downstream targets such as STAT5, RAS, phosphatidylinositol-3′-kinase (PI3K), and others [7–10]. Many studies have shown that constitutive activation of the gene Signal Transducers and Activators of Transcription 5 (STAT5) plays an important role in the pathogenesis of CML induced by BCR–ABL [11–14], as well as in acute myeloid leukemias (AML) [15–17] and in polycythemia rubra vera [18,19]. STAT5 is the component of a family of seven proteins (STAT1-6) critical for the pathogenesis of many tumors [20–22], but these proteins are largely dispensable in normal adult cells [23], suggesting that they could be targets with a high therapeutic index[24–26].…”

Section: Introductionmentioning

confidence: 99%

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation

Romagnoli

Baraldi

Prencipe

et al. 2016

European Journal of Medicinal Chemistry

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Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3′,4′,5′-trimethoxybenzoyl)-3-iodoacetamido-6-methoxybenzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3′,4′,5′-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR–ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.

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The role of the STAT5 proteins in the proliferation and apoptosis of the CML and AML cells

Abstract: Our studies showed that the STAT5 proteins may be critical in the regulation of growth and apoptosis of the CML and AML leukaemic cells.

Cited by 40 publications

References 41 publications

Multidomain Targeting of Bcr-Abl by Disruption of Oligomerization and Tyrosine Kinase Inhibition: Toward Eradication of CML

Multidomain Targeting of Bcr-Abl by Disruption of Oligomerization and Tyrosine Kinase Inhibition: Toward Eradication of CML

Involvement of the STAT5 Signaling Pathway in the Regulation of Mouse Preimplantation Development

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation

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