Prognostic and therapeutic role of targetable lesions in B-lineage acute lymphoblastic leukemia without recurrent fusion genes

// Monica Messina 1,* , Sabina Chiaretti 1,* , Jiguang Wang 2,* , Anna Lucia Fedullo 1 , Nadia Peragine 1 , Valentina Gianfelici 1 , Alfonso Piciocchi 3 , Fulvia Brugnoletti 1 , Filomena Di Giacomo 4 , Simona Pauselli 1 , Antony B. Holmes 5 , Maria Cristina Puzzolo 1 , Giulia Ceglie 1 , Valerio Apicella 1 , Marco Mancini 1 , Geertruy te Kronnie 6 , Anna Maria Testi 1 , Antonella Vitale 1 , Marco Vignetti 3 , Anna Guarini 1 , Raul Rabadan 2 and Robin Foa 1 1 Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy 2 Department of Systems Biology, Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA 3 GIMEMA Data Center, Rome, Italy 4 Department of Molecular Biotechnology and Health Science, and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy 5 Institute for Cancer Genetics and The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA 6 Department of Women’s and Children’s Health, University of Padova, Padova, Italy * These authors have contributed equally to this work Correspondence to: Robin Foa, email: // Keywords : acute lymphoblastic leukemia, next generation sequencing, copy number aberrations, novel prognostic markers, genetic-driven targeted therapy Received : October 23, 2015 Accepted : January 28, 2016 Published : February 12, 2016 Abstract To shed light into the molecular bases of B-lineage acute lymphoblastic leukemia lacking known fusion transcripts, i.e. BCR-ABL1 , ETV6-RUNX1 , E2A-PBX1 , and MLL rearrangements (B-NEG ALL) and the differences between children, adolescents/young adults (AYA) and adults, we analyzed 168 B-NEG ALLs by genome-wide technologies. This approach showed that B-NEG cases carry 10.5 mutations and 9.1 copy-number aberrations/sample. The most frequently mutated druggable pathways were those pertaining to RAS/RTK (26.8%) and JAK/STAT (12.5%) signaling. In particular, FLT3 and JAK/STAT mutations were detected mainly in AYA and adults, while KRAS and NRAS mutations were more frequent in children. RAS/RTK mutations negatively affected the outcome of AYA and adults, but not that of children. Furthermore, adult B-NEG ALL carrying JAK/STAT mutations had a shorter survival. In vitro experiments showed that FLT3 inhibitors reduced significantly the proliferation of FLT3 -mutated primary B-NEG ALL cells. Likewise, PI3K/mTOR inhibitors reduced the proliferation of primary cells harboring RAS and IL7R mutations. These results refine the genetic landscape of B-NEG ALL and suggest that the different distribution of lesions and their prognostic impact might sustain the diverse outcome between children, adults and partly AYA - whose genomic scenario is similar to adults - and open the way to targeted therapeutic strategies.