PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia

Goswami, Swagata; Mani, Rajeswaran; Nunes, Jessica; Chiang, Chi‐Ling; Zapolnik, Kevan; Hu, Eileen; Frissora, Frank; Mo, Xiaokui; Walker, Logan A.; Yan, Pearlly S.; Bundschuh, Ralf; Beaver, Larry; Devine, Raymond D.; Tsai, Yo‐Ting; Ventura, Ann; Xie, Zhiliang; Chen, Min; Lapalombella, Rosa; Walker, Alison; Mims, Alice S.; Larkin, Karilyn; Grieselhuber, Nicole R.; Bennett, Chad E.; Phelps, Mitch A.; Hertlein, Erin; Behbehani, Gregory K.; Vasu, Sumithira; Byrd, John C.; Muthusamy, Natarajan

doi:10.1182/blood.2020010344

Cited by 22 publications

(10 citation statements)

References 89 publications

(159 reference statements)

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“…It is reported that activated STATs family proteins are known to regulate the target gene’s transcription and act as transcription factors [ 35 ]. More importantly, c-Myc can restrain the expression of p21 [ 36 , 37 ].We wondered if p-STAT6 regulated the expression of c-Myc as a transcription factor. We detected the location of p-STAT6 and c-Myc by IF assay.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we confirmed that inhibition of p-STAT6 resulted in G2/M phase arrest, accompanied by the increase of p21 protein but no obvious change of p27 in P190 cell lines. The oncogene c-Myc promotes cell cycle progression of tumor cells partly by inhibiting the synthesis of p21 [ 36 , 37 ]. We found that the transcription and protein levels of c-Myc were reduced when p-STAT6 was inhibited.…”

Section: Discussionmentioning

confidence: 99%

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Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190BCR-ABL

Qin

Wang

et al. 2023

Cell Commun Signal

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Background The Philadelphia chromosome encodes the BCR-ABL fusion protein, which has two primary subtypes, P210 and P190. P210 and P190 cause Philadelphia-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), respectively. The Ph+ ALL is more malignant than Ph+ CML in disease phenotype and progression. This implies the key pathogenic molecules and regulatory mechanisms caused by BCR-ABL in two types of leukemia are different. It is reported that STAT6 was significantly activated only in P190 transformed cells. However, the potential role and the mechanism of STAT6 activation in Ph+ ALL and its activation mechanism by P190 are still unknown. Methods The protein and mRNA levels of STAT6, c-Myc, and other molecules were measured by western blot and quantitative real-time PCR. The STAT6 inhibitor AS1517499 was used to specifically inhibit p-STAT6. The effect of p-STAT6 inhibition on Ph+ CML and Ph+ ALL cells was identified by CCK-8 and FCM assay. Dual luciferase reporter and ChIP assay were performed to confirm the direct binding between STAT6 and c-Myc. The impact of STAT6 inhibition on tumor progression was detected in Ph+ CML and Ph+ ALL mouse models. Results Our results demonstrated that P210 induced CML-like disease, and P190 caused the more malignant ALL-like disease in mouse models. STAT6 was activated in P190 cell lines but not in P210 cell lines. Inhibition of STAT6 suppressed the malignancy of Ph+ ALL in vitro and in vivo, whereas it had little effect on Ph+ CML. We confirmed that p-STAT6 regulated the transcription of c-Myc, and STAT6 was phosphorylated by p-Jak2 in P190 cell lines, which accounted for the discrepant expression of p-STAT6 in P190 and P210 cell lines. STAT6 inhibition synergized with imatinib in Ph+ ALL cells. Conclusions Our study suggests that STAT6 activation plays an essential role in the development of Ph+ ALL and may be a potential therapeutic target in Ph+ ALL.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190BCR-ABL

Qin

Wang

et al. 2023

Cell Commun Signal

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“…In addition, we have recently reported the ability of C c to modulate PP2A activity by interacting with another PP2A inhibitor, namely ANP32B [49] . A potential role for C c regulating tumor progression by inducing PP2A release from its inhibitors SET/TAF-Iβ or ANP32B cannot be discarded, as disruption of PP2A inhibition by targeting SET/TAF-Iβ hinders the progression of certain kinds of tumors [38] , [85] , [86] . In this context, it is tempting to propose a plausible function for SET/TAF-Iβ and/or ANP32B in INTAC-mediated transcription, as well as a clear impact of nuclear C c over INTAC activity and its consequences in tumor development.…”

Section: Discussionmentioning

confidence: 99%

PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ

Casado-Combreras

Rivero-Rodríguez

Elena-Real

et al. 2022

Computational and Structural Biotechnology Journal

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“…An important serine/threonine phosphatase, PP2A can regulate the cell cycle by controlling the G1/S transition. Its central role as a regulator of the cell cycle revealed its function as a tumor regulator 35 . Through a PP2A activity assay, we found that PG promoted the activity of PP2A in GBM cells, which led to dephosphorylation of Akt.…”

Section: Discussionmentioning

confidence: 99%

Prodigiosin inhibits the proliferation of glioblastoma by regulating the KIAA1524/PP2A signaling pathway

Zhao

Gao

Ning

et al. 2022

Sci Rep

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Prodigiosin (PG), a member of a family of natural red pigments produced by a variety of bacteria, was first discovered in Serratia marcescens. PG has been reported to have an apoptosis-inducing effect in many cancers, such as lymphoma, colon cancer and nasopharyngeal carcinoma. For this study, we used three glioblastoma (GBM) cell lines (LN229, U251 and A172) to explore the effect of prodigiosin on GBM cells. A CCK8 assay was used to evaluate cell viability. We determinedthe cell cycle distribution by flow cytometry and measured proliferation by an EdU incorporation assay. The expression of different molecules was investigated by western blotting and RT-PCR. We further confirmed our results by plasmid transfection and lentiviral transduction. The LN229 xenograft model was used to study the effect of prodigiosin in vivo. We confirmed that prodigiosin played an anticancer role in several GBM cell lines through the KIAA1524/PP2A/Akt signalling pathway. Prodigiosin inhibited the protein expression of KIAA1524 by suppressing its transcription, which led to activation of PP2A. Afterward, PP2A inhibited the phosphorylation of Akt, thereby inducing increased expression of p53/p21. Furthermore, it was verified that prodigiosin inhibited the KIAA1524/PP2A/Akt axis in vivo in the LN229 xenograft model. These data improve the understanding of the anticancer effects of prodigiosin and further highlight the potential of prodigiosin for the development of anti-glioma drugs.

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PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia

Cited by 22 publications

References 89 publications

Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190BCR-ABL

Jak2/STAT6/c-Myc pathway is vital to the pathogenicity of Philadelphia-positive acute lymphoblastic leukemia caused by P190BCR-ABL

PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ

Prodigiosin inhibits the proliferation of glioblastoma by regulating the KIAA1524/PP2A signaling pathway

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