TY - JOUR
T1 - Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia
AU - Fabbri, Giulia
AU - Holmes, Antony B.
AU - Viganotti, Mara
AU - Scuoppo, Claudio
AU - Belver, Laura
AU - Herranz, Daniel
AU - Yan, Xiao Jie
AU - Kieso, Yasmine
AU - Rossi, Davide
AU - Gaidano, Gianluca
AU - Chiorazzi, Nicholas
AU - Ferrando, Adolfo A.
AU - Dalla-Favera, Riccardo
N1 - Funding Information:
We thank Jon Aster for providing the NOTCH1 antisera used for ChIP-Seq of NOTCH1 in chronic lymphocytic leukemia cells; Ben K. Seon for the MO1043 cell line; Elias Campo and Jennifer Brown for sharing useful information; and the Genomic Technologies Shared Resource for sequencing the ChIP-Seq and the RNA-Seq libraries. This work was supported by the US National Institutes of Health Grant R01-CA177319 (to R.D.-F. and A.A.F.); Special Program Molecular Clinical Oncology 5 x 1000 No. 10007, Associazione Italiana per la Ricerca sul Cancro Foundation Milan, Italy and Progetto Ricerca Finalizzata RF-2011-02349712, Ministero della Salute, Rome, Italy (to G.G.); National Institutes of Health Grant K99/R00 CA197869 and an Alex's Lemonade Stand Foundation Young Investigator grant (to D.H.); and a Leukemia and Lymphoma Society Fellowship (to C.S.).
PY - 2017/4/4
Y1 - 2017/4/4
N2 - Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ?4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ?50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.
AB - Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ?4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ?50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.
KW - Chronic lymphocytic leukemia
KW - NOTCH1
KW - Transcriptional network
UR - https://www.scopus.com/pages/publications/85016978871
U2 - 10.1073/pnas.1702564114
DO - 10.1073/pnas.1702564114
M3 - Article
SN - 0027-8424
VL - 114
SP - E2911-E2919
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -