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Jan Cools

"We try to understand
the genetic complexity of leukemia,
with the aim to use that information
to develop novel treatment strategies."

Leukemia is a genetically complex disease that is caused by the accumulation of chromosomal rearrangements and mutations in the genome of immature blood cells. These abnormal blood cells slowly outcompete the normal blood cells and infiltrate in various tissues, causing faillure of normal function.

The Laboratory for the Molecular Biology of Leukemia has identified and characterized important oncogenes and tumor suppressor genes in both myeloid and lymphoid leukemias, and has used that information to develop novel treatment strategies.

We have initially focused on the study of chronic eosinophilic leukemia, which is characterized by the presence of a chromosomal deletion leading to the generation of the FIP1L1-PDGFRA oncogene. Our work has contributed to the identification and characterization of this oncogene and has led to the improved survival of these leukemia patients by treatment with the targeted small molecule inhibitor imatinib, which specifically inhibits the oncogenic activity of FIP1L1-PDGFRA. It is rewarding to see that our discovery helps patients with eosinophilia and other tumor types, as reported recently for this patient with a rare type of sarcoma.

Since 2004, we have also studied the genetic defects in T-cell acute lymphoblastic leukemia. We identified the NUP214-ABL1 oncogene, as well as several other oncogenes and tumor suppressor genes (MYB, RPL5, RPL10, CNOT3, JAK3). Read here how this discovery is offering new hope for leukemia patients.

The  aim of our current project is to understand the genetic complexity of acute lymphoblastic leukemia (ALL), and to understand how several oncogenes cooperate with each other during leukemogenesis. These insights can lead to the development of improved therapeutic strategies.

The main focus of our work is on T-cell acute lymphoblastic leukemia (T-ALL), an aggressive T-cell malignancy that is most common in children and adolescents.

We aim to identify novel oncogenic events in T-ALL using next-generation sequencing technologies. Mutations in RPL5, RPL10 and CNOT3 were recently identified in our exome sequencing study and targeted resequencing of 155 T-ALL cases revealed an important role for the interleukin-7 receptor/JAK1/JAK3 signaling complex as it is mutated in 26% of T-ALL.

Mutations in the interleukin-7 receptor/JAK/STAT pathway are important drivers of T-ALL development. We are studying the mechanisms by which these oncogenes are transforming T-cells using cell-based assays and mouse leukemia models.

T-ALL samples contain specific combinations of mutations, suggesting that those oncogenes cooperate with each other during the development and progression of the leukemias. We are studying the mechanism of cooperation between different oncogenes to identify new possible avenues to target T-ALL.



Karen Vousden, Paolo Sassone-Corsi, Christian Frezza, Nika Danial
12/09/2017 - 09:00