Morgana acts as an oncosuppressor in chronic myeloid leukemia

Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.

show abstract

“…Immunohistochemistry experiments were performed on formalin-fixed, paraffin-embedded tissues from n = 5 patients, as previously reported [60]. …”

Section: Methodsmentioning

confidence: 99%

Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Rho-associated coiled-coil kinases (ROCKs) are major effectors of the small GTPase RHOA, the important role of ROCK in cancer progression including cell metastasis has been demonstrated by thousands of studies (21)(22)(23). Moreover, ROCK inhibitors such as Y-27632 (24) or fasudil (25) have also been widely studied in various cancer cell lines and animal models and showed significant benefits when used along (26)(27)(28) or combined with other chemotherapy drugs (29)(30)(31). Though the role of ROCK2 in basic studies was no questioned, only one clinical trial using ROCK2 inhibitor AT13148 in cancer treatment was reported in 2012 (ClinicalTrials.gov identifier NCT01585701).…”

Section: Discussionmentioning

confidence: 99%

LncRNA ZFAS1 promotes pancreatic adenocarcinoma metastasis by sponging miR-3924 via RHOA/ROCK2 pathway

Liu

Zhu

2020

Preprint

View full text Add to dashboard Cite

Background : the mortality and morbidity rate of pancreatic adenocarcinoma has been increasing during the past two decades, mechanisms in pancreatic adenocarcinoma progression are in urgent need of research. LncRNA ZFAS1 has been demonstrated as an oncogene in some cancers, but its function and mechanism in pancreatic adenocarcinoma still remain unclear. Methods : ZFAS1 expression level was predicted in pancreatic adenocarcinoma by bioinformatic analysis, the expression level of ZFAS1 in pancreatic adenocarcinoma tissues and cell lines were further investigated by qRT-PCR and ISH. The functions of ZFAS1 on pancreatic adenocarcinoma in vitro and in vivo were investigated according to bioinformatic analysis. Dual luciferase report assays investigated the binding of ZFAS1/miR-3924 and miR-3924/ROCK2, rescue assays further investigated the underlying mechanism. Results: ZFAS1 was predicted and further experimental verified to be over-expressed in pancreatic adenocarcinoma. ZFAS1 silence showed the inhibition to pancreatic adenocarcinoma metastasis in vitro and in vivo. The competing endogenous RNAs mechanism of ZFAS1 was also demonstrated. Conclusions : Our results demonstrated the promotion of ZFAS1 to pancreatic adenocarcinoma metastasis and suggested its candidacy as a novel regulator of ROCK2.

show abstract

“…ROCKs are major effectors of the small GTPase RHOA, and the important roles of ROCK in cancer progression, including in cell metasta sis, have been demonstrated by thousands of studies (23)(24)(25). Moreover, ROCK inhibitors such as Y-27632 (26) and fasudil (27) have also been widely studied in various cancer cell lines and animal models and have shown signi cant bene ts when used alone (28)(29)(30) or in combination with other chemotherapeutic drugs (31)(32)(33). Although the role of ROCK2 shown in basic studies has not been questioned, only one clinical trial using the ROCK2 inhibi tor AT13148 for cancer treatment was reported in 2012 (ClinicalTrials.gov identi er NCT01585701).…”

Section: Discussionmentioning

confidence: 99%

LncRNA ZFAS1 promotes pancreatic adenocarcinoma metastasis via the RHOA/ROCK2 pathway by sponging miR-3924

Liu

Zhu

2020

Preprint

View full text Add to dashboard Cite

Background: The mortality and morbidity rates of pancreatic adenocarcinoma have been increasing over the past two decades, and an understanding of the mechanisms underlying pancreatic adenocarcinoma progression is urgently needed. The long non-coding RNA ZFAS1 has been demonstrated to be an oncogene in some cancers, but its function and mechanism in pancreatic adenocarcinoma remain unclear.Methods: The ZFAS1 expression level in pancreatic adenocarcinoma was predicted by bioinformatic analysis, and the expression level of ZFAS1 in pancreatic adenocarcinoma tissue samples and cell lines was further investigated by quantitative real-time PCR and in situ hybridization. The functions of ZFAS1 in pancreatic adenocarcinoma in vitro and in vivo were investigated by further bioinformatic analysis. Dual-luciferase reporter assays were used to investigate the binding of ZFAS1/miR-3924 and miR-3924/ROCK2, and rescue assays were performed to further investigate the underlying mechanism.Results: ZFAS1 overexpression in pancreatic adenocarcinoma was predicted and experimentally verified. ZFAS1 silencing inhibited pancreatic adenocarcinoma metastasis in vitro and in vivo. The competing endogenous RNA mechanism of ZFAS1 was also identified.Conclusions: Our results demonstrated the promotive effect of ZFAS1 on pancreatic adenocarcinoma metastasis and suggested its potential role as a novel regulator of ROCK2.

show abstract

Morgana acts as an oncosuppressor in chronic myeloid leukemia

Abstract: Key Points Morgana haploinsufficiency in mice causes a lethal and transplantable CML-like myeloid neoplasm. Morgana is underexpressed in aCML and in a subgroup of CMLs, where it predicts a worse response to imatinib but sensitivity to ROCK inhibitors.

Cited by 22 publications

References 50 publications

Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

LncRNA ZFAS1 promotes pancreatic adenocarcinoma metastasis by sponging miR-3924 via RHOA/ROCK2 pathway

LncRNA ZFAS1 promotes pancreatic adenocarcinoma metastasis via the RHOA/ROCK2 pathway by sponging miR-3924

Contact Info

Product

Resources

About