The role of STATs in myeloid differentiation and leukemia

Coffer, Paul J.; Koenderman, Leo; Groot, Rolf P. de

doi:10.1038/sj.onc.1203479

Cited by 200 publications

(138 citation statements)

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“…Constitutive activated STAT3 has been found in several malignancies, including AML, multiple myeloma, head and neck cancers and many others Co er et al, 2000;Lin et al, 2000;Song and Grandis, 2000). In some cases, oncogenic tyrosine kinases, including v-Src, vEyk and v-Ros, activate STAT3 in the absence of (a) Stable NIH3T3 cells expressing MEN2A-RET, MEN2A-RET and STAT3a or MEN2A-RET and STAT3b were generated as described in the Materials and methods section.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a role of STAT3 in oncogenesis has been identi®ed in a number of studies. In various tumours, including leukaemias, lymphomas, breast cancers, and head and neck cancers, a constitutive activation of STAT3 has been observed in the absence of ligand stimulation Co er et al, 2000;Lin et al, 2000;Schuringa et al, 2000b;Song and Grandis, 2000). In some cases, oncogenic tyrosine kinases like v-src activate STAT3 and induce cellular transformation in a STAT3-dependent manner (Bromberg et al, 1998;Cao et al, 1996;Turkson et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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MEN2A-RET-induced cellular transformation by activation of STAT3

et al. 2001

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The MEN2A oncogene encodes for a constitutive active member of the RET receptor tyrosine kinase family. Here, we report that MEN2A-RET activates Signal Transducer and Activator of Transcription 3 (STAT3) via two YxxV/Q STAT3 docking sites, Tyr752 and Tyr928. MEN2A-RET induces both Tyr705 and Ser727 phosphorylation of STAT3, and STAT3 serine phosphorylation is required for its maximal transcriptional activity. Stable NIH3T3 cell lines expressing both MEN2A-RET and STAT3a but not STAT3b, are characterized by enhanced proliferation and cyclin-D1 promoter activity, and enhanced growth in soft agar. These data indicate that malignant cell growth induced by MEN2A-RET involves its activation of STAT3. Oncogene (2001) 20, 5350 ± 5358.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MEN2A-RET-induced cellular transformation by activation of STAT3

et al. 2001

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“…As the list of human tumors that harbor constitutive Stat3 activity keeps growing, there is increasing chance that many more cases of human cancers will be identi®ed in which Stat3 has prominent role in the induction and/or maintenance of the oncogenic phenotype. Constitutive Stat3 tyrosine or serine phosphorylation has been detected in breast carcinomas (Garcia et al, 1997(Garcia et al, , 2000Watson and Miller, 1995), head and neck squamous cell carcinomas (Grandis et al, 1998(Grandis et al, , 2000aSong and Grandis, 2000), as well as lymphomas and leukemias (Catlett-Falcone et al, 1999a,b, 2000Co er et al, 2000;Frank et al, 1997;GouilleuxGruart et al, 1996;Weber-Nordt et al, 1996;Zhang et al, 1996c). Other cases of tumors with constitutive Stat3 activity include prostate, melanoma, pancreas, ovarian and brain (Cattaneo et al, 1998;Florenes et al, 1999;Kirkwood et al, 1999;Lou et al, 2000;Magrassi et al, 1999;Pansky et al, 2000;Schrell et al, 1998; L Mora, R Garcia, J Seigne, T Bowman, G Niu, J Pow-Sang, J Diaz, C Muro-Cacho, D Coppola, T Yeatman, J Cheng, S Nicosia, S Shivers, T Landowski, D Reintgen, W Dalton, H Yu and R Jove, unpublished results).…”

Section: Stat3 Activation and Human Diseasesmentioning

confidence: 99%

STAT proteins: novel molecular targets for cancer drug discovery

2000

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“…15,16 Despite these reports, expression of Bcl-2 has not been found to correlate significantly with other prognostic indicators in AML, such as cytogenetic alterations 13 or FLT3 mutation. However, Bcl-2 family members are transcriptional targets of STAT protein transcription factors Stat5 and Stat3 in AML cells, 17 suggesting that observed alterations in leukemic cell signaling via STATs 1 might cause the overexpression of Bcl-2 and allow AML blasts to evade apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53

Irish

Ånensen

Hovland

et al. 2006

Blood

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Loss or mutation of the TP53 tumor suppressor gene is not commonly observed in acute myeloid leukemia (AML), suggesting that there is an alternate route for cell transformation. We investigated the hypothesis that previously observed Bcl-2 family member overexpression suppresses wild-type p53 activity in AML. We demonstrate that wild-type p53 protein is expressed in primary leukemic blasts from patients with de novo AML using 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and phospho-specific flow cytometry. We found that p53 was heterogeneously expressed and phosphorylated in AML patient samples and could accumulate following DNA damage. Overexpression of antiapoptosis protein Bcl-2 in AML cells was directly correlated with p53 expression and phosphorylation on serine residues 15, 46, and 392. Within those patients with the highest levels of Bcl-2 expression, we identified a mutation in FLT3 that duplicated phosphorylation site Y591. The presence of this mutation correlated with greater than normal IntroductionWe have previously reported that signaling profiles of acute myeloid leukemia (AML) cells identify patients with a poor response to course one of chemotherapy. 1 In that study we showed that mutation of fms-like tyrosine kinase 3 (Flt3) was associated with increased activity of signal transduction and activator of transcription (STAT) family members Stat5 and Stat3, but we did not explore how this signaling might contribute to the observed therapy resistance. Here we examine the connection between a target of altered Stat5 signaling in AML-the Bcl-2 protein-and the suppression of normal apoptotic responses to DNA damage in leukemia cells. Evasion of apoptosis contributes to the formation and continued survival of cancer cells 2 and insight into signaling mechanisms that suppress apoptosis in AML cells could be used to improve the efficacy of existing therapies. 3 AML is particularly relevant to the study of suppressed apoptotic pathways in cancer because p53, a central driver of apoptosis and guardian of genomic integrity, is not generally lost or mutated in this disease. 4,5 p53 is a sequence-specific transcription factor that can halt progression through the cell cycle or initiate apoptosis. 6 Furthermore, p53 is a key tumor suppressor protein often lost or mutated in human cancers; however, TP53 has been reported to be mutant in only 7% of AML cases. 4 Subsequent research has also shown that downstream p53 effector genes, such as p21, are rarely lost in AML and that wild-type p53 protein is expressed in newly established AML derived cell lines. 7 For this study, we measured several properties of p53 in primary AML cells, including TP53 gene sequence, per-cell abundance of p53 protein, and p53 phosphorylation at 5 residues. 8 Following DNA damage and cell stresses, p53 protein is rapidly phosphorylated at several residues, 9 including those we measured here (serines 15, 20, 37, 46, and 392). Phosphorylation of p53 is thought to regulate p53 localization, conformation, and activity, 10 but t...

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The role of STATs in myeloid differentiation and leukemia

Cited by 200 publications

References 138 publications

MEN2A-RET-induced cellular transformation by activation of STAT3

MEN2A-RET-induced cellular transformation by activation of STAT3

STAT proteins: novel molecular targets for cancer drug discovery

Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53

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