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

• Published in: Oncotarget Vol. 7; no. 12; pp. 13886 - 13901
• Main Authors: Messina, Monica, Chiaretti, Sabina, Wang, Jiguang, Fedullo, Anna Lucia, Peragine, Nadia, Gianfelici, Valentina, Piciocchi, Alfonso, Brugnoletti, Fulvia, Di Giacomo, Filomena, Pauselli, Simona, Holmes, Antony B., Puzzolo, Maria Cristina, Ceglie, Giulia, Apicella, Valerio, Mancini, Marco, te Kronnie, Geertruy, Testi, Anna Maria, Vitale, Antonella, Vignetti, Marco, Guarini, Anna, Rabadan, Raul, Foà, Robin
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 22.03.2016
• Subjects: Adolescent; Adult; Aged; Biomarkers, Tumor - genetics; Cell Lineage; Child; Child, Preschool; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Infant; Male; Middle Aged; Mutation; Neoplasm Staging; Oncogene Proteins, Fusion - genetics; Polymorphism, Single Nucleotide; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - mortality; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prognosis; Research Paper; Survival Rate; Young Adult; copy number aberrations; genetic-driven targeted therapy; novel prognostic markers; acute lymphoblastic leukemia; next generation sequencing
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7356

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.