CIP2A high expression is a poor prognostic factor in normal karyotype acute myeloid leukemia

Barragán, Eva; Chillón, María Carmen; Castelló-Cros, Remedios; Marcotegui, Nerea; Prieto, M.; Hoyos, Montserrat; Pippa, Raffaella; Llop, Marta; Etxabe, Amaia; Cervera, José; Rodrı́guez, Gabriela; Buño, Ismael; Rifón, J.; Sierra, Jorge; González, Marcos; Calasanz, Marı́a José; Sanz, Miguel Á.; Odero, Marı́a D.

doi:10.3324/haematol.2014.118117

Cited by 20 publications

(28 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results showed that the anti-leukaemia activity of carfilzomib is not necessarily dependent on its proteasome inhibition (Fig 2C-E). Instead, the sensitivity of leukaemia cells was significantly correlated with KIAA1524 levels (Figs 3-4).The clinical relevance of KIAA1524 in leukaemia has been reported recently (Lucas et al, 2011;Wang et al, 2011;Barragan et al, 2015). Carfilzomib, alone or in combination with chemotherapy is currently undergoing several early phase trials for the treatment of relapsed or refractory leukaemia (NCT clinical trials: NCT01137747, NCT02303821, NCT02512926).…”

Section: Discussionmentioning

confidence: 86%

“…KIAA1524 was found to be aberrantly expressed in various malignancies and associated with poor prognosis (Vaarala et al, 2010;Bockelman et al, 2011Bockelman et al, , 2012Wang et al, 2011;Xu et al, 2012). KIAA1524 has been identified as a key determinant of disease progression in chronic myeloid leukaemia (CML) (Lucas et al, 2011), and a prognostic factor in normal cytogenetic acute myeloid leukaemia (AML) (Barragan et al, 2015), suggesting that KIAA1524 could be a therapeutic target in leukaemia. However, the impact of KIAA1524 targeting and the associated molecular events in leukaemia remain to be determined.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

et al. 2017

View full text Add to dashboard Cite

Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.

show abstract

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Decreased PP2A tumor suppressor activity due to an increased expression of PAIPs has been reported to promote malignant growth of several cell types 9, 25 , including leukemic cells 10 . In AML, SET promotes both malignant growth and drug resistance 17, 26 , and CIP2A inhibition in AML cells reduces proliferation and MYC expression 27 . Prevalent role for PP2A inhibition in AML 10 , and in other cancer types 9, 25 , provides a strong scientific rationale for clinical association between low ARPP19 expression and a lower risk for AML relapse newly discovered in this study.…”

Section: Discussionmentioning

confidence: 99%

ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia

Mäkelä

Löyttyniemi

Salmenniemi

et al. 2019

Preprint

View full text Add to dashboard Cite

24Despite of extensive genetic analysis of acute myeloid leukemia (AML), we still 25 do not understand comprehensively mechanism that promote disease relapse 26 from standard chemotherapy. Based on recent indications for non-genomic 27 inhibition of tumor suppressor protein phosphatase 2A (PP2A) in AML, we 28 examined mRNA expression of PP2A inhibitor proteins in AML patient samples. 29Notably, out of examined PP2A inhibitor proteins, overexpression of ARPP19 30 mRNA was found independent of current AML risk classification. Functionally, 31 ARPP19 promoted AML cell viability and expression of oncoproteins MYC, 32 CDK1, and another PP2A inhibitor CIP2A. Clinically, ARPP19 mRNA expression 33 was significantly lower at diagnosis (p=0.035) in patients whose disease did not 34 relapse after standard chemotherapy. ARPP19 was an independent predictor for 35 relapse both in univariable (p=0.007) and in multivariable analyses (p=0.0001); 36 and gave additive information to EVI1 expression and risk group status (additive 37 effect, p=0.005). Low ARPP19 expression also associated with better patient 38 outcome in TCGA LAML cohort (p=0.019). In addition, in matched patient 39 samples from diagnosis, remission and relapse phases, ARPP19 expression 40 associated with disease activity (p=0.034). 41Together, these data identify ARPP19 as a novel oncogenic PP2A inhibitor 42 protein in AML, and demonstrate its risk group independent role in predicting AML 43 patient relapse tendency. 44 45 46 3

show abstract

“…Junttila et al (2007) Overexpression in hematological and solid tumors(Barragán et al, 2015;Côme et al, 2009;Junttila et al, 2007;Kerosuo et al, 2010;Khanna et al, 2015;W. Li, Zhang, Yang, & Wang, 2019) PME1 PPME1 or PP2A-specific methylesterase 1 CXing et al (2008) Role in tumor growth (J Li et al, 2014;.…”

mentioning

confidence: 99%

Data mining analysis of the PP2A cell cycle axis in mesothelioma patients

Pippa

Boffo

Odero

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

Mesothelioma is an aggressive tumor that affects thousands of people every year. The therapeutic options for patients are limited; hence, a better understanding of mesothelioma biology is crucial to improve patient survival. To find new molecular targets and therapeutic strategies related to the protein phosphatase 2A (PP2A) network, we analyzed the gene expression of known PP2A inhibitors in mesothelioma patient samples. Our analysis disclosed a general overexpression of all PP2A‐negative regulators in mesothelioma patients. Moreover, the expression of ANP32E and CIP2A genes, increased in 16% and 11% of cases, positively correlates with the ones of all the other PP2A regulators and the ones of the main cyclins and CDKs, suggesting the existence of a feed‐forward loop that might contribute to the mesothelioma progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (ANP32E and CIP2A) and cell cycle regulators (cyclin B2/CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve mesothelioma patient survival.

show abstract

CIP2A high expression is a poor prognostic factor in normal karyotype acute myeloid leukemia

Cited by 20 publications

References 14 publications

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia

Data mining analysis of the PP2A cell cycle axis in mesothelioma patients

Contact Info

Product

Resources

About