An Inv(16)(p13.3q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein Defines an Aggressive Subtype of Pediatric Acute Megakaryoblastic Leukemia

• Published in: Cancer cell Vol. 22; no. 5; pp. 683 - 697
• Main Authors: Gruber, Tanja A., Larson Gedman, Amanda, Zhang, Jinghui, Koss, Cary S., Marada, Suresh, Ta, Huy Q., Chen, Shann-Ching, Su, Xiaoping, Ogden, Stacey K., Dang, Jinjun, Wu, Gang, Gupta, Vedant, Andersson, Anna K., Pounds, Stanley, Shi, Lei, Easton, John, Barbato, Michael I., Mulder, Heather L., Manne, Jayanthi, Wang, Jianmin, Rusch, Michael, Ranade, Swati, Ganti, Ramapriya, Parker, Matthew, Ma, Jing, Radtke, Ina, Ding, Li, Cazzaniga, Giovanni, Biondi, Andrea, Kornblau, Steven M., Ravandi, Farhad, Kantarjian, Hagop, Nimer, Stephen D., Döhner, Konstanze, Döhner, Hartmut, Ley, Timothy J., Ballerini, Paola, Shurtleff, Sheila, Tomizawa, Daisuke, Adachi, Souichi, Hayashi, Yasuhide, Tawa, Akio, Shih, Lee-Yung, Liang, Der-Cherng, Rubnitz, Jeffrey E., Pui, Ching-Hon, Mardis, Elaine R., Wilson, Richard K., Downing, James R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.11.2012
• Subjects: Animals; Bone Morphogenetic Proteins - metabolism; Child; Chromosome Inversion; Chromosomes, Human, Pair 16; Drosophila - genetics; Drosophila - growth & development; Gene Expression Profiling; Humans; Kruppel-Like Transcription Factors - genetics; Leukemia, Megakaryoblastic, Acute - classification; Leukemia, Megakaryoblastic, Acute - diagnosis; Leukemia, Megakaryoblastic, Acute - genetics; Mice; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncogene Proteins, Fusion - physiology; Prognosis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - physiology; Repressor Proteins - genetics; Sequence Analysis, RNA; Signal Transduction; Tumor Suppressor Proteins - genetics
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2012.10.007

To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis. ► CBFA2T3-GLIS2 is a recurrent fusion gene in pediatric AMKL ► CBFA2T3-GLIS2 AMKL has a distinct expression profile and an inferior outcome ► CBFA2T3-GLIS2 induces BMP signaling and enhanced self-renewal of progenitor cells