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

2016; Impact Journals LLC; Volume: 7; Issue: 12 Linguagem: Inglês

10.18632/oncotarget.7356

1949-2553

Monica Messina, Sabina Chiaretti, Jiguang Wang, Anna Lucia Fedullo, Nadia Peragine, Valentina Gianfelici, Alfonso Piciocchi, Fulvia Brugnoletti, Filomena Di Giacomo, Simona Pauselli, Antony B. Holmes, Maria Cristina Puzzolo, Giulia Ceglie, Valerio Apicella, Marco Mancini, Geertruy te Kronnie, Anna Maria Testi, Antonella Vitale, Marco Vignetti, Anna Guarini, Raúl Rabadán, Robin Foà,

Acute Myeloid Leukemia Research

// 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 Foà 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 Foà, 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.