Abstract 4507: New JAK2 heterozygous loss: A role in overall survival in acute myeloid leukemia patients
Authors: Guadagnuolo Viviana , Fontana Maria Chiara , Papayannidis Cristina , Manfrini Marco , Padella Antonella , Simonetti Giorgia , Ferrari Anna , Marconi Giovanni , Ghelli Luserna di Rorà Andrea , Paolini Stefania , Abbenante MariaChiara , Parisi Sarah , Sartor Chiara , Ottaviani Emanuela , Martinelli Giovanni 
Published: July 2016

Abstract
Acute Myeloid Leukemia (AML) is a clonal hematopoietic disorder characterized by an abnormal proliferation and differentiation of immature blast cells in the bone marrow.
SNP microarray approach has resulted in genome-wide screening for genomic alterations with information not previously achievable and also it allows to map all the genes involved in these alterations which may plays a role in oncogenesis.
Our objective is to evaluate the prognostic impact of these genetic alterations on clinical outcome.
We analyzed 285 AML samples at diagnosis of which 221 by SNP Array 6.0 (Affymetrix) (Affymetrix), while 64 by by CytoScan HD Array (Affymetrix). The results obtained were analyzed by Chromosome Analysis Suite (ChAS) v1.2 (Affymetrix Inc.) and Nexus Copy Number™ v7.5 softwares (BioDiscovery).
The 285 AML patients (pts) analyzed are equally distributed between both sexes, they have a median age of 60 years, include miscellaneous cytogenetic abnormalities and normal karyotype. The 44% of pts are treated with chemotherapy (CHT), the 16% of pts with low-dose cytosine arabinoside, the 20% of pts with 5-azacytidine and the 19% of pts are not treated or had only supportive therapy. The ratio between responders and non responders pts was 57/43. Each pt presented an average of 1448 events so distributed: 31% of homozygous deletions, 32% of homozygous amplifications, while irrelevant events are related to heterozygous deletions and amplifications. We also found 36% of uniparental disomy (UPD)events.
Among all these macroscopic and submicroscopic alterations, we focused on JAK2 gene, which is located on human chromosome 9 at p24.1 locus. It is composed of 25 exons and encodes a 1132 amino-acid protein of 130.7 kDa.
This gene was amplified in 12/285 pts (4%) and deleted in 13/285 (5%). All these pts are treated with CHT but only those characterized by JAK2 deletion are responsive in first line. We showed that the group of pts which present this deletion had a better overall survival rate than the group with the amplification of this gene (p-value &lt; 0,01).
The deletion event of JAK2 gene involved two different regions: the first region had a length of 7.429 bp involving the intron 4 and was found in the database genome variant (DGV); the second deletion presented a variable length between different pts: the smallest deleted region had a length of 3342 bp and included the exons 17, 18, 19, while the largest one had a length of 76903 bp which included the portion from exon 9 to exon 19. This second deletion has not been described in DGV and it involved the pseudokinase and kinase domain of JAK2 protein.
We have identified Copy Number Variation involving important cancer genes in AML. We have identified a new JAK2 deletion involving its Pseudokinase and Kinase domain and we observed that this deletion of JAK2 correleted with overall survival.
ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project
Citation Format: Viviana Guadagnuolo, Maria Chiara Fontana, Cristina Papayannidis, Marco Manfrini, Antonella Padella, Giorgia Simonetti, Anna Ferrari, Giovanni Marconi, Andrea Ghelli Luserna di Rorà, Stefania Paolini, MariaChiara Abbenante, Sarah Parisi, Chiara Sartor, Emanuela Ottaviani, Giovanni Martinelli. New JAK2 heterozygous loss: A role in overall survival in acute myeloid leukemia patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4507.