Jan Cools
Molecular Pathogenesis of Leukemia
VIB Department of Molecular and Developmental Genetics, K.U.Leuven

PhD: Univ. of Leuven, Leuven, Belgium, ‘01 Postdoc: Harvard Medical School, Boston, USA, ‘01-‘03 VIB Group leader since 2008

e-mail Phone + 32 16 33 00 82 ADDRESS

Current team members
Group leader: Jan Cools
Postdoctoral scientists: Idoya Lahortiga, Kim De Keersmaecker, Lijs Beke, Luk Cox, Piotr Zabrocki, Rikkert Snoeckx
Ph.D. Students: Daphnie Pauwels, Leila Rouhi Gharabei, Maria Kleppe, Michaël Porcu, Sofie Pieraets, Zeynep Kalender
Support personnel: Bram Sweron, Ellen Geerdens, Els Beullens, Kris Jacobs, Nicole Mentens, Olga Gielen, Roel Vandepoel, Sonja Van Genechten

Keywords
leukemia - oncogene - tyrosine kinase - therapy - drug screen

Science

Short description
We try to better understand the genetic cause of leukemia, to be able 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 purpose and risk stratification, but translation of current genetic insights towards therapeutic applications is currently limited. The general aim of our projects is to identify novel oncogenic mutations, to study the potential of targeting these deregulated pathways for leukemia therapy, and to study the cooperation of oncogenes during leukemogenesis in order to further improve therapeutic strategies.
We aim to identify novel oncogenic events in leukemia using genome-wide molecular strategies (array CGH, SNP arrays, next generation sequencing), or through functional screens (RNAi and chemical screens). A special focus will be on signaling pathways that may be involved in the proliferation and survival of the leukemic cells. As models for our studies, we use chronic eosinophilic leukemia (CEL), as a model for a genetically ‘simple’ leukemia, and T-cell acute lymphoblastic leukemia (T-ALL), as a model for a genetically ‘complex’ leukemia.

T-cell acute lymphoblastic leukemia (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%. At least 4 different types of mutations can be identified simultaneously in specific T-ALL cases and cell lines, suggesting that leukemic transformation of developing thymocytes is caused by a multistep process involving various mutations that affect proliferation/survival, differentiation, cell-cycle control, and stem-cell maintenance. The mutations providing the proliferation and survival advantage of T-ALL cells remain unknown in 70 % of the cases.

Chronic eosinophilic leukemia (CEL) is a clonal myeloproliferative disease characterized by an overproduction of eosinophils in the bone marrow with subsequent eosinophilia in the peripheral blood, and infiltration of eosinophils in tissues. A common cause of CEL is expression of the FIP1L1-PDGFRa protein, a constitutively active tyrosine kinase that provides a proliferative and survival advantage to the leukemic cells. FIP1L1-PDGFRa can be inhibited by the tyrosine kinase inhibitor imatinib, which forms the basis for the current treatment of CEL. Some CEL patients, however, progress towards an imatinib resistant disease, which remains difficult to treat. Some CEL patients lack the FIP1L1-PDGFRA fusion, and the cause of the eosinophilia in these patients remains unknown.

Press releases
See also press release (17/05/2010): Gene loss causes leukemia based on a publication in Nature Genetics (Kleppe et al., Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia, Nature Genetics, 2010).

See also press release (14/07/2008): Not the protein, but its location in the cell, determines the onset of leukemia - based on a publication in Molecular Cell (De Keersmaecker et al., Molecular Cell, 2008).

Kleppe 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 J
Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia
NAT GENET 42, 530-5, 2010



De 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 J
Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear pore
MOL CELL 31, 134-42, 2008



Lahortiga I, De Keersmaecker K, Van Vlierberghe P, Graux C, Cauwelier B, Lambert F, Mentens N, Beverloo H, Pieters R, Speleman F, Odero M, Bauters M, Froyen G, Marynen P, Vandenberghe P, Wlodarska I, Meijerink J, Cools J
Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia
NAT GENET 39, 593-595, 2007



Lierman E, Folens C, Stover E, Mentens N, Van Miegroet H, Scheers W, Boogaerts M, Vandenberghe P, Marynen P, Cools J
Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant
BLOOD 108, 1374-6, 2006



Stover E, Chen J, Folens C, Lee B, Mentens N, Marynen P, Williams I, Gilliland D, Cools J
Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent
P NATL ACAD SCI USA 103, 8078-83, 2006

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