We try to understand the genetic causes of leukemia, and to use that information to develop novel treatment strategies.
Molecular analysis of leukemias has identified a large number of specific chromosomal defects and oncogenes. This information is used for diagnostic purposes and for risk stratification, but the translation of current genetic insights into therapeutic applications is limited. The general aim of our project is to study the development of leukemia and to develop novel treatment strategies.
We have recently identified several novel oncogenic events in T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing, RNAi screens and chemical screens. T-ALL is an aggressive T-cell malignancy that is most common in children and adolescents. Improvement of treatment regimens has led to significant increases in survival, but long-term survival rates for adult T-ALL patients are still below 40%. Using exome sequencing, we have identified on average 8 mutations in childhood T-ALL and 21 mutations in adult T-ALL, indicating that leukemic transformation of developing thymocytes is caused by a multi-step process involving various mutations that affect proliferation/survival, differentiation, cell-cycle control, chromatine structure and stem-cell maintenance. We are currently analyzing the oncogenic properties of specific candidate oncogenes such as JAK3 and CNOT3, and are developing cell-based models and mouse models to determine how these oncogenes cooperate with other oncogenic events.
JAK3 mutants transform hematopoietic cells through JAK1 activation causing T-cell acute lymphoblastic leukemia in a bone marrow transplant mouse modelDegryse S, De Bock C, Cox L, Demeyer S, Gielen O, Mentens N, Jacobs K, Geerdens E, Gianfelici V, Hulselmans G, Fiers M, Aerts S, Meijerink J, Tousseyn T, Cools JBLOOD, e-pub, e-pub, 2014 Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemiaDe Keersmaecker K, Atak Z, Li N, Vicente C, Patchett S, Girardi T, Gianfelici V, Geerdens E, Clappier E, Porcu M, Lahortiga I, Lucà R, Yan J, Hulselmans G, Vranckx H, Vandepoel R, Sweron B, Jacobs K, Mentens N, Wlodarska I, Cauwelier B, Cloos J, Soulier J, Uyttebroeck A, Bagni C, Hassan B, Vandenberghe P, Johnson A, Aerts S, Cools JNATURE GENETICS, 45, 186-90, 2013 PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemiaKleppe M, Soulier J, Asnafi V, Mentens N, Hornakova T, Knoops L, Constantinescu S, Sigaux F, Meijerink J, Vandenberghe P, Tartaglia M, Foa R, Macintyre E, Haferlach T, Cools JBLOOD, 117, 7090-8, 2011 Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemiaKleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C, Van Roosbroeck K, Ferrando A, Langerak A, Meijerink J, Sigaux F, Haferlach T, Wlodarska I, Vandenberghe P, Soulier J, Cools JNATURE GENETICS, 42, 530-5, 2010 Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear poreDe Keersmaecker K, Rocnik J, Bernad R, Lee B, Leeman D, Gielen O, Verachtert H, Folens C, Munck S, Marynen P, Fornerod M, Gilliland D, Cools JMOLECULAR CELL, 31, 134-42, 2008
09/12/2013 - ERC-grants grants for three VIB scientists: boost for innovative research
23/12/2012 - In collaboration with international research teams, scientists at VIB, KU Leuven and UZ Leuven have unmasked the ribosome – the molecular machine in the cell that is involved in the production of proteins – as a weak spot in leukemia cells.
05/01/2012 - VIB and BGI are organising a genomics meeting on 15 Feb 2012 in Leuven, Belgium. Executives and investigators from both institutions will share their expertise on large scale genomcs and computational analysis
17/05/2010 - Researchers from VIB and K.U.Leuven have discovered a new factor in the development of acute lymphoblastic leukemia.
08/07/2008 - Not the protein, but its location in the cell, determines the onset of leukemia
13/04/2007 - Scientists are still searching for the cause of many forms of leukemia, including T-cell acute lymphoblastic leukemia, or T-ALL.
PhD: University of Leuven, Leuven, Belgium, 2001
Postdoc.: Harvard Medical School, Boston, USA, 2001-03
VIB Group leader since 2008