Abstract 4835: A new biomarker of response to 5-azacitidine therapy in MDS and AML patients: SIRPB1
Authors: Guadagnuolo Viviana , Papayannidis Cristina , Iacobucci Ilaria , Simonetti Giorgia , Padella Antonella , Paolini Stefania , Abbenante Mariachiara , Parisi Sarah , Volpato Francesca , Sartor Chiara , Fontana Maria Chiara , Delledonne Massimo , Malagola Michele , Filì Carla , Russo Domenico , Grilli Sandro , Cavo Michele , Martinelli Giovanni 
Published: August 2015

Introduction: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are a group of diseases of the elderly that initiates in a hematopoietic stem cell and are characterized by clonal hematopoiesis and uncertain prognosis, mostly due to cytogenetic background. In both diseases, 5-azacitidine (5-Aza) has been successful, inducing prolonged survival and delayed AML evolution.

Aim: To identify the genes mostly predictive of treatment response, we use high-throughput genomic analysis (SNP arrays and/or NGS-RNA-seq and/or NGS-WES) in azacitidine-sensitive and resistant MDS/AML patients.

Materials and Methods: NGS-WES or RNA seq HiSeq 2000 (Illumina) was positively done in 35/214 AML samples (16%). SNPs arrays (CytoScan HD Array, Affymetrix Inc.) was done in 125/214 AML samples (58%) and 18/32 MDS samples (56%) at diagnosis, then analyzed by Chromosome Analysis Suite (ChAS) v1.2 (Affymetrix Inc.), Nexus Copy Number™ v7.5 (BioDiscovery) and GeneGo MetaCore™ software.

Results: We treated 246 adult patients (pts) with MDS or AML: 214 pts were AML and 32 were MDS with a median age of 59 and 70 years, respectively. Forty-five pts were treated with 5-Aza (32 MDS / 13 AML), while 201 AML were treated with conventional chemotherapy.

Forty-five MDS/AML pts were treated with at least one complete cycle of 5-Aza (75 mg/sqm/daily). SNP arrays was done in 22/45 (49%), 13 pts were defined “insensitive/resistant”. Macroscopic CNAs affecting a complete chromosome or its arms were detected in 5 of 22 pts (23%), while classical cytogenetic was able to detect only two cases of trisomy 8 (9%), suggesting superiority of SNPs array for CNAs identifications. Chromosomic aberrations disease-related are more statistically frequent on pts “insensitive” versus pts. “sensitive” (64% vs. 35%) (p≤0.01).

Moreover we found that from the median of chromosomic alterations lenghts (in kbp) the group of “insensitive” MDS/AML patients to 5-Aza therapy present more losses than “sensitive” ones.

By Nexus Copy Number software, we identify 137 genes highly differentially gain (SIRPB1 and KIT with p ≤ 0.05) or loss (SIRPB1, LCE1C, BCAS1, EXD3 with p ≤ 0.05) or LOH between “insensitive” versus “sensitive” to 5-Aza (p ≤ 0.05). Among these genes, we focused on SIRPB1 (cytoband 20p13, 56Kbps), since it was loss on 14/22 (64%) “insensitive” pts (p = 0,023) and gain on 7/22 (32%) “sensitive” ones (p = 0,0324), respectively. SIRPB1 common deletion region length is 27 kbps and the common amplified region length is 30 kbps.

By NGS-WES we analyzed 35/214 (16%) AML samples at diagnosis. We found mutations in SF3B1, NPM1, CBL, RUNX1, BCOR, KIT, GATA2, IDH2, KDM6A, KIAA1324L, PRIM2, RRN3, APOBR and again in SIRPB1 an heterozygous missense variant (rs45545343; p. H/D).

Conclusions:

We conclude that SIRPB1 is a promising marker of response to 5-Aza treatment in myelodysplastic syndromes and in acute myeloid leukemia.

Citation Format: Viviana Guadagnuolo, Cristina Papayannidis, Ilaria Iacobucci, Giorgia Simonetti, Antonella Padella, Stefania Paolini, Mariachiara Abbenante, Sarah Parisi, Francesca Volpato, Chiara Sartor, Maria Chiara Fontana, Massimo Delledonne, Michele Malagola, Carla Filì, Domenico Russo, Sandro Grilli, Michele Cavo, Giovanni Martinelli. A new biomarker of response to 5-azacitidine therapy in MDS and AML patients: SIRPB1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4835. doi:10.1158/1538-7445.AM2015-4835