scholarly journals Alterations in Pathways Regulating Phosphatidil Inositol 3 Phosphate (PI3P) Produce Both Cell Proliferation and Therapy Resistance, and Define a Group of Patients with Poor Prognosis in Acute Myeloid Leukemia (AML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1679-1679
Author(s):  
Giovanni Marconi ◽  
Cristina Papayannidis ◽  
Maria Chiara Fontana ◽  
Antonella Padella ◽  
Giorgia Simonetti ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Multivariable Analysis ◽  
Therapy Resistance ◽  
Comparative Genomic ◽  
Complex Karyotype ◽  
Secondary Aml ◽  
Hr Model

Abstract Introduction PI3P is a key regulator of cell growth, and mediates cell proliferation via PI3K/AKT/mTOR in response to various growth signals. Abnormal activation of genes in its pathway is associated to oncogenic activity and poor Overall Survival (OS). PI3P is also a core activator of autophagy. Which role autophagy plays in cancer is not well established; it can function as a pro-apoptotic mechanism, or it can improve survive to stresses clearing damaged mitochondria and proteins accumulation, preventing apoptosis. Levels and activity of pro-apoptotic and anti-apoptotic proteins, particularly bcl-2 and p53, membrane signaling via mTOR, high levels of cAMP, a complex made by pink/park, promote a switch from apoptotic autophagy toward a mechanism that augment cell resiliency. Our study aims to define the role of PI3P pathways in AML, and to establish if autophagy could reduce the patients' chance to respond to induction, and to worsen OS. Methods We analyzed 208 consecutive newly diagnosed non M3 AML patients, screened for TP53, FLT3, NMP1, IDH1, IDH2, and DNMT3A mutations. Remission status was assessed with bone marrow biopsy. In all the patients, we perform Microarray-based Comparative Genomic Hybridization with Affymetrix SNP array 6.0 or Cytoscan HD; we perform Whole Exome Sequencing (WES)in 80/208 patients. Survival data were collected prospectively, with a median follow-up of 18 months. Survival analysis was performed with Kaplan Meyer method using log rank test. Univariate and multivariable regression and Cox Hazard Ratio(HR) model was performed. Correlation between variables was assessed with Fisher's exact test. Results We analyzed 4 pathways (Table 1); we selected genes in pathways basing on literature and GO data. Alterations in these pathways involved 103/209 patients (48%). PI3K/AKT/mTOR pathway alterations (both gains or losses) were shown to confer worst OS (p = .035, Figure 1a) when compared with unaltered patients; events in these pathways did not affect therapy response. Autophagy pathway alterations were shown to confer worst OS (p<.001, Figure 1b); alterations of autophagy were related to lower Complete Remission rate (CR%) after induction in univariate (p<.001) and multivariable regrassion with age, karyotype, secondary AML, TP53 mutation (p=0.014). Autophagy was significantly altered in patients with complex karyotype and TP53 mutation (p<.001). AMPK pathway alterations were shown to confer worst OS (p<.001, Figure 1c); Alteration of regulators in cAMP were related to lower CR% after induction in univariate (p<.001) and multivariable analysis with age, karyotype, secondary AML, TP53 mutation (p=0.009). AMPc pathway alteration was significantly associated with complex karyotype and TP53 mutation (p<.001). Autophagy switch pathway confer worst OS to patients(p<.001, figure 1d); autophagy switch was related to lower CR% after induction in univariate (p<.001) and multivariable analysis with age, karyotype, secondary AML (p<0.001). Autophagy switch was an independent risk factor in optimal Cox-HR model (p<.001, HR 2.996, CI 95% 2.101-4.271). Alterations in PINK or PARK did not showed to affect prognosis alone. Having at least an altered pathway is associated with worst prognosis (p <.001), and poor CR% after induction in univariate(p=.009) and multivariable analysis (p=.014). WES in a sub-cohort of patients did not found any significant mutation in genes we analyzed. This data is consistent with literature. Conclusions Our work investigates for the first time the role of PI3P pathways and autophagy in AML. Surprisingly, it showed that both positive and negative alterations in these pathways are associated with poor prognosis. Significantly, alterations in cAMP and autophagy pathways were associated with therapy resistance. These results point out that both positive and negative regulation of autophagy could worsen patients OS; a diminished autophagy could be linked to a hyper-proliferative state via activation of AKT/mTOR but an augmented autophagy could give cell resiliency, favoring cytoplasm turnover, damaged mitochondria elimination, and neutralizing oxidative damages to proteins. A pan-PI3K inhibitor could target these mechanisms and improve chemo-sensitivity in high risk AML. Acknowledgment: ELN, AIL, AIRC, PRIN, Progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures Guadagnuolo: CellPly S.r.l.: Employment. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; MSD: Consultancy; Ariad: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Genentech: Consultancy; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

scholarly journals The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 439 ◽  
Author(s):  
Vanessa Delcroix ◽  
Olivier Mauduit ◽  
Nolwenn Tessier ◽  
Anaïs Montillaud ◽  
Tom Lesluyes ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Therapy Resistance ◽  
High Grade ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Well Differentiated

By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS.

scholarly journals Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

Oncogene ◽  
2019 ◽  
Vol 39 (6) ◽  
pp. 1185-1197 ◽  
Author(s):  
Mónica López-Guerra ◽  
Sílvia Xargay-Torrent ◽  
Patricia Fuentes ◽  
Jocabed Roldán ◽  
Blanca González-Farré ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Notch Signaling ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Target Genes ◽  
Notch Signaling Pathway ◽  
Lymphocytic Leukemia ◽  
Therapeutic Targeting ◽  
Notch Ligand

Abstract Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

scholarly journals miR-202 Suppresses Cell Proliferation by Targeting FOXR2 in Endometrial Adenocarcinoma

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Xinchao Deng ◽  
Congzhe Hou ◽  
Zhen Liang ◽  
Huali Wang ◽  
Lin Zhu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Poor Prognosis ◽  
Endometrial Adenocarcinoma ◽  
Luciferase Reporter ◽  
Candidate Target ◽  
Candidate Target Gene

Background. MicroRNA-202 (miR-202) has been reported to be aberrantly regulated in several cancers. The aim of this study is to explore the functional role of miR-202 in EAC tumor growth. Material and Methods. miR-202 expression was detected by qRT-PCR. TargetScan and luciferase reporter assay were used to elucidate the candidate target gene of miR-202. The FOXR2 protein level was assessed by Western blot and immunohistochemistry. Survival analysis was explored for FOXR2 expression in EAC patients. Results. miR-202 expression was significantly decreased in EAC tissues (P<0.01) compared with that in control tissues. And the downregulate miR-202 was significantly associated with poor prognosis (P<0.01). Re-expression of miR-202 dramatically suppressed cell proliferation in vitro and tumor growth in vivo. FOXR2 was identified as a direct target of miR-202. In EAC tissues, FOXR2 was upregulated and the increased FOXR2 was significantly associated with poor prognosis. In miR-202-transfected cells, the FOXR2 expression was inversely changed. The analysis of FOXR2 protein expression and miR-202 transcription in EAC tissues showed negative correlation (R=−0.429). Conclusion. miR-202 may function as a tumor suppressor in EAC tumor growth by targeting FOXR2 oncogene, which may provide new insights into the molecular mechanism and new targets for treatment of EAC.

scholarly journals LOXL1-AS1 predicts poor prognosis and promotes cell proliferation, migration, and invasion in osteosarcoma

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Si Chen ◽  
Weiguo Li ◽  
Ai Guo
Keyword(s):  
Cell Proliferation ◽  
Overall Survival ◽  
Poor Prognosis ◽  
Histological Grade ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Loss Of Function ◽  
Osteoblast Cell Line ◽  
Enneking Stage

Abstract lncRNA LOXL1 antisense RNA 1 (lncRNA LOXL1-AS1) was recently found to function as oncogenic lncRNA in glioblastoma, prostate cancer, and medulloblastoma. The role of LOXL1-AS1 in osteosarcoma was still unknown. In our study, we found LOXL1-AS1 expression levels were higher in osteosarcoma tissues and cell lines than normal bone tissues and normal osteoblast cell line, respectively. Moreover, high-expression of LOXL1-AS1 was correlated with Enneking stage, tumor size, distant metastasis, histological grade, and overall survival time in osteosarcoma patients. Furthermore, LOXL1-AS1 overexpression acted as an independent poor predictor for overall survival in osteosarcoma patients. The loss-of-function studies showed knockdown of LOXL1-AS1 dramatically inhibited osteosarcoma cell proliferation, migration, and invasion through suppressing PI3K-AKT pathway. In conclusion, LOXL1-AS1 predicts clinical progression and poor prognosis in osteosarcoma patients and functions as oncogenic lncRNA to regulate cell proliferation, cell cycle, migration, and invasion.

Prognostic significance of alterations of pathways regulating autophagy in acute myeloid leukemia.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7038-7038 ◽  
Author(s):  
Giovanni Marconi ◽  
Maria Chiara Fontana ◽  
Cristina Papayannidis ◽  
Antonella Padella ◽  
Silvia Lo Monaco ◽  
...  
Keyword(s):  
Survival Data ◽  
Tp53 Mutation ◽  
Prognostic Significance ◽  
Snp Array ◽  
Physiological Role ◽  
Therapy Resistance ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

7038 Background: Nowadays, science is debating if autophagy in cancer can lead to therapy resistance or it can favor apoptosis. Autophagy pathways are involved pro-apoptotic mechanism, or they can improve stresses survival eliminating damaged mitochondria and proteins. Levels and activity of pro-apoptotic and anti-apoptotic proteins (eg. bcl-2 and p53), high levels of cAMP, and a pink/park complex could play as fulcrum on this lever. Our study aims to define the role of autophagy in AML. Methods: We analyzed 148 consecutive non M3 AML with Affymetrix SNP array. We screened all patients for TP53, FLT3, NMP1 mutations. Patients was treated with intensive induction chemotherapy regimens. Survival data were collected prospectively, with a median follow-up of 18 months. Results: Autophagy alteration (gene group 1: ULK1 CHR11; ULK1 CHR17; BECN1; ATG14; AMBRA1; UVRAG; ATG9A; ATG9B; PIK3C3; PIK3R4) was related to lower Complete Remission rate (CR%) after induction in univariate (p < .001) and multivariable regression model with age, karyotype, secondary AML, TP53 mutation (p = .014); autophagy alteration shown to confer worst Overal Survival (OS) (p < .001) and was significantly associated with complex karyotype and TP53 mutation (p < .001). We detected significant differences in term of survival independently both in gain and loss in group 1 genes (p < .001). Alterations in genes in cAMP pathway (group 2: SESN1; PRKAA1 CHR 3; PRKAB1: PRKAA1 CHR 1: PRKAG1 CHR11; PRKAG1 CHR 7; PRKAG3; PRKAB1) and in genes that could be related to a switch from a physiological role of autophagy to a resiliency mechanism (group 3: CCND1; BCL2; PINK1; PARK2; TP53; MDM1; MDM4) showed to confer worst OS (p < .001 in both groups); Alteration in group 2 and group 3 were related to lower CR% after induction (p < .001 in both groups). Whole Exome Sequencing on 56 patients in our set did not found any significant mutation in genes we analyzed with the exception of TP53. Conclusions: Alterations in autophagy regulator genes are associated with poor prognosis and therapy resistance. A loss in autophagy could block apoptosis, a gain could confer cell resiliency. Acknowledgements: ELN, AIL, AIRC, Progetto Regione-Università 2010-12,FP7 NGS-PTL, HARMONY

scholarly journals Upregulation of far upstream element-binding protein 1 (FUBP1) promotes tumor proliferation and unfavorable prognosis in tongue squamous cell carcinoma

2020 ◽  
Vol 35 (2) ◽  
pp. 56-65
Author(s):  
Yang Chen ◽  
Jiameng Liu ◽  
Ningbo Geng ◽  
Chongjin Feng
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Western Blot ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Poor Prognosis ◽  
Qrt Pcr ◽  
Upstream Element

Background: A well-known transcriptional regulator of the proto-oncogene c-Myc, far-upstream element (FUSE) binding protein 1 (FUBP1) has been demonstrated by previous work to be aberrantly expressed in lots of cancers and plays a critical role in tumor progression; however, its expression and function in tongue squamous cell carcinoma (TSCC) remains unclear. Methods: Evaluations with immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to assess FUBP1 expression. The correlations of FUBP1 expression levels with various clinicopathological factors were evaluated with univariate and multivariate analyses. In addition, the role of FUBP1 in TSCC proliferation was studied in TSCC cells by silencing FUBP1. The role of FUBP1 on proliferation and apoptosis was confirmed by cell counting Kit-8, colony formation, cell cycle, and cell apoptosis assays. Results: Immunohistochemistry, qRT-PCR and Western blot results showed FUBP1 expression was higher in TSCC tissues in comparison with adjacent non-cancerous tissues ( P <0.05), as well as in patients with advanced-stage disease or cervical lymph node metastasis ( P<0.001). The 5-year survival rate was significantly lower in the group with high FUBP1 expression than in that with low FUBP1 expression ( P=0.035). FUBP1 expression was also an independent predictor for overall survival in TSCC patients, and was closely related to poor prognosis. FUBP1 knockdown inhibited cancer cell proliferation, and induced cell cycle arrest and apoptosis. Conclusion: FUBP1 was overexpressed in TSCC, and correlated with TSCC cell proliferation and poor prognosis. FUBP1 appears to act as a potential oncogene in TSCC, and may be considered a novel biomarker for TSCC.

Cullin-1 Promotes Cell Proliferation in Human Breast Cancer and is Related to Diabetes

2016 ◽  
Vol 31 (4) ◽  
pp. 375-381
Author(s):  
Yun-Hai Zhou ◽  
Jiazeng Xia ◽  
Wen-Huan Xu ◽  
Xiqi Zhu ◽  
Xiao-Hong Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Disease Free Survival ◽  
Ubiquitin Proteasome System ◽  
Cycle Progression ◽  
Previous Diagnosis ◽  
Ubiquitin Proteasome ◽  
Clinicopathological Variables

Aim Breast carcinoma (BCA) and diabetes mellitus (DM) are two major health problems in women and the general population. Cullin-1 is reported to be an important tumor-related protein involved in cell-cycle progression, signal transduction and transcription. The aim of this work is to investigate the role of Cullin-1 in the development of BCA and to find potential relationships between Cullin-1 and diabetes in BCA patients. Methods To evaluate the function of Cullin-1, we entered 168 patients with primary invasive BCA in this study. Pairs of BCA tissues and adjacent noncancerous tissues from these patients were collected between 2006 and 2008. We used immunohistochemistry to analyze the correlation between Cullin-1 expression and clinicopathological variables and patient survival. In addition, we investigated the role of Cullin-1 in BCA cell proliferation. Results Cullin-1 expression was upregulated in BCA tissues. Enhanced immunoreactivity for Cullin-1 in BCA tissues was inversely correlated with overall survival and disease-free survival, which suggested a poor prognosis in BCA patients. Strong expression of Cullin-1 was more frequently observed in patients with estrogen receptor negativity and HER2 positivity. We also found that Cullin-1 expression was increased in BCA patients with a previous diagnosis of diabetes. Conclusions Our results demonstrate that increased Cullin-1 expression is significantly correlated with poor prognosis in patients with BCA. Cullin-1 might regulate BCA cell proliferation through the ubiquitin-proteasome system. Thus, Cullin-1 might be an important marker and a therapeutic target in BCA.

scholarly journals TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Pimjai Niparuck ◽  
Pornnapa Police ◽  
Phichchapha Noikongdee ◽  
Kanchana Siriputtanapong ◽  
Nittaya Limsuwanachot ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Objectives TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients. Discussion In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

scholarly journals TP53 Mutation in Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Syndrome

2021 ◽  
Author(s):  
Pimjai Niparuck ◽  
Pornnapa Police ◽  
Phichchapha Noikongdee ◽  
Kanchana Siriputtanapong ◽  
Nittaya Limsuwanachot ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Objectives: TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods: Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results: A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66%, 13%, 9%, 9% and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50%, 17.6%, 9.2% and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22% and 27%, respectively. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P= 0.023, HR= 1.20- 7.02), whereas, WBC count> 100,000/μL (P= 0.004, HR= 1.32- 4.16) and complex karyotype (P= 0.038, HR= 1.07- 9.78) were associated with shorter OS in AML patients. Discussion: In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

scholarly journals Chromothripsis in Acute Myeloid Leukemia Is Strongly Associated with Poor Prognosis and TP53 Alterations

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1678-1678
Author(s):  
Maria Chiara Fontana ◽  
Giovanni Marconi ◽  
Jelena D. Milosevic Feenstra ◽  
Cristina Papayannidis ◽  
Marco Manfrini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genomic Instability ◽  
Copy Number ◽  
Driving Force ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract Introduction Genomic instability and complex karyotype are linked to chemoresistance, poor prognosis and early relapse rate in Acute Myeloid Leukemia (AML). Chromothripsis, a one-step catastrophic mechanism of genomic instability, could represent a driving force in the development and progression of hematological diseases and could be identified by high throughput technologies as Single Nucleotide Polymorphism (SNP) Array. We investigate the mechanisms involved in chromothripsis in newly diagnosed non M3-AML patients (patients) in order to better characterize a class of very high risk patients that could be candidate to innovative therapies. Methods We performed classical cytogenetic and microarray analysis (SNP Arrays 6.0 or Cytoscan HD Arrays, Affymetrix) in 418 AML samples. Data were analyzed by Nexus Copy Number™ and R Core Team. Chromothripsis-like patterns were confirmed by CTLP Scanner (Log Ratio ≥ 8, ≥ 10 switches, minimum segment size of 10 kb, distance between adjacent fragments ≤ 10% and 0.3 as variation from different copy number (CN) states). Overall survival was analyzed by Kaplan-Meier method and Mantel-Cox test. Results Twenty-six/418 patients (6.2%) showed chromothripsis involving different chromosomes. Chromosome 12 (23%), 17 (19%) and 5 (19%) were the most affected, followed by chromosomes 3, 6, 7, 8, 10, 11, 13, 15 and 20. Patients harboring chromothripsis had a higher median age compared with chromothripsis-negative ones (70.4 vs. 55 years, respectively, p<.001) and a lower white blood cells (WBC) count at diagnosis (4,395 vs. 30,000, respectively, p =.019). The group of patients with chromothripsis presented a prevalence of complex karyotype (p<.001) and high risk (HR) disease according to ELN definition (p<.001). Furthermore, we found a significantly higher incidence of TP53 mutation (p<.001) in chromothripsis-positive patients: 16/26 patients had an heterozygous loss of 17p13 (p<.001) and 21/24 harbored a TP53 mutation (2 samples were not evaluated) . TP53 loss and mutation co-occurred in 20 cases. Chromothripsis-positive patients showed an extremely poor prognosis compared with chromothripsis-negative ones (median survival of 120 vs. 526 days, respectively, p<.001) and a 3.4 risk of death at Cox-hazard ratio analysis (C.I. 95%: 1.85-6.27). Moreover, chromothripsis showed to predict a lower response rate independently of age at diagnosis, de novo/secondary AML, FLT3 mutational status and type of induction therapy (p=.044). Of note, chromothripsis was associated with worst prognosis even if compared with HR karyotype features without chromothripsis (median survival of 120 and 265 days, respectively, p<.001, Figure 1). Finally, by comparing patients with and without chromothripsis, we identified several genes and pathways differentially altered between the 2 groups (p<0.001). Chromothripsis was particularly associated with loss of RAD50, FANCA, MARCH3, WNT8A, SHH, BCL2, USP34, CTNNA1, with 5q being the main altered chromosomic region, while ZFPM2 was the main amplified gene. Conclusion Our results demonstrate that chromothripsis is a recurrent event in adult AML and independently defines a group of patients with poor prognosis. Chromothripsis is strongly associated with TP53 alterations in AML and for the first time, we define incidence and survivals of chromothripsis in a set of 418 newly diagnosed consecutive AML patients. Chromosomal abnormalities like chromothripsis could be a driving force in the development of cancer as well in hematological disease like AML, in which the genomic instability represent the main scenario. Since TP53 is known to deregulate Fanconi Anaemia genes, the deregulation of DNA double-strand break repair could sustain the maintenance of catastrophic mechanism like chromothripsis. Acknowledgment ELN, AIL, AIRC, PRIN, Progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project. MCF and GM equal contribution Disclosures Kralovics: Qiagen: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Research Funding. Martinelli:Novartis: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; MSD: Consultancy; Genentech: Consultancy; Pfizer: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Roche: Consultancy, Speakers Bureau.

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