Abstract 3311: The alteration in key regulator genes of autophagy is mainstream mechanism of therapy resistance and impact prognosis of acute myelogenous leukemia (AML): results from diagnosis genomic analysis on 148 consecutive patients treated with intensive chemotherapy and long-term survival follow-up

Abstract

Abstract Introduction There are no clear evidences if autophagy can lead to therapy resistance or favor apoptosis in cancer; it can function as a pro-apoptotic mechanism, or it can improve stresses survival clearing damaged mitochondria and proteins accumulation. Levels and activity of pro-apoptotic and anti-apoptotic proteins, particularly bcl-2 and p53, high levels of cAMP, and a complex made by pink/park could play as fulcrum of this yin and yang effect of autophagy. Our study aims to define the role of autophagy in AML, and to establish if gain or loss in autophagy could reduce the patients’ chance to respond to induction, and to worsen OS. Methods We analyzed 148 consecutive newly diagnosed non M3 AML patients treated with induction chemotherapy regimens containing at least one dose of anthracycline. We screened all patients for TP53, FLT3, NMP1 mutations; we performed Affymetrix SNP array 6.0 or Cytoscan HD. 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) were related to lower Complete Remission rate (CR%) after induction in univariate (p<.001) and multivariable regression with age, karyotype, secondary AML, TP53 mutation (p=.014); autophagy alteration shown to confer worst 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). Furthermore, we investigated genes in AMPK pathway (group 2: SESN1; PRKAA1 CHR 3; PRKAB1: PRKAA1 CHR 1: PRKAG1 CHR11; PRKAG1 CHR 7; PRKAG3; PRKAB1) and other 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): alterations in those genes were shown 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 Our work investigates for the first time with a genomic approach the role of autophagy in AML. We found that both gain and loss in autophagy key regulator genes are associated with poor prognosis and therapy resistance. A loss in autophagy could enhance proliferation and block apoptosis; a gain could give cell resiliency, favoring cytoplasm turnover, damaged mitochondria elimination, and neutralizing oxidative damages. Acknowledgements: ELN, AIL, AIRC, PRIN, Progetto Regione-Università 2010-12, FP7 NGS-PTL project. Citation Format: Giovanni Marconi, Cristina Papayannidis, Maria Chiara Fontana, Antonella Padella, Anna Ferrari, Eugenia Franchini, Stefania Paolini, Maria Chiara Abbenante, Chiara Sartor, Francesca Volpato, Viviana Guadagnuolo, Silvia Lo Monaco, Elena Tenti, Andrea Ghelli Luserna Di Rora, Valentina Robustelli, Nicoletta Testoni, Giorgia Simonetti, Emanuela Ottaviani, Giovanni Martinelli. The alteration in key regulator genes of autophagy is mainstream mechanism of therapy resistance and impact prognosis of acute myelogenous leukemia (AML): results from diagnosis genomic analysis on 148 consecutive patients treated with intensive chemotherapy and long-term survival follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3311. doi:10.1158/1538-7445.AM2017-3311