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Mutations in the JAK2 Tyrosine Kinase in Children with Down Syndrome Acute Lymphoblastic Leukemia
| Third-party funded project |
| Project title |
Mutations in the JAK2 Tyrosine Kinase in Children with Down Syndrome Acute Lymphoblastic Leukemia |
| Principal Investigator(s) |
Skoda, Radek C.
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| Organisation / Research unit |
Departement Biomedizin / Experimental Hematology (Skoda) |
| Project start |
01.10.2010 |
| Probable end |
30.09.2012 |
| Status |
Completed |
| Abstract |
Children with Down syndrome (DS) have a markedly increased risk of both myeloid and lymphoblastic leukemia. The incidence of acute myeloid leukemia (AML) in children with Down Syndrome is 500-fold higher than in the general population, while the incidence of acute lymphoblastic leukemia (ALL) is approximately 20-fold higher. The prognosis of DS-AML is excellent on contemporary protocols, with an approximately 80% cure rate. However, the prognosis of DS-ALL is less favorable. Recently, mutations at position 683 of the Jak2 protein (e.g. JAK2-R683G) were described in at least 20% of patients with DS-ALL. These mutations are distinct from those seen in patients with myeloproliferative neoplasm (MPN), which reside at position 617 (JAK2-V617F). This lead to the hypothesis that the location of the JAK2 mutation might determine the phenotype by affecting different downstream signaling events. Furthermore, CRLF2, a receptor expressed on B-lymphocytes, was found to be overexpressed in about 60% of DS-ALL. These findings defined new potential drug targets and inhibitors of the Jak2 kinase have already been developed that are currently undergoing clinical trials in patients with MPN.
To define the role of the JAK2-R683G in the pathogenesis of B cell ALL we developed a transgenic mouse model that expresses the JAK2-R683G mutation. Using this mouse model we propose to address the following specific aims:
1. Is JAK2-R683G sufficient to cause the B cell ALL? Why is the molecular aberration restricted to the B cell lineage?
2. Is there a synergism between mutated JAK2-R683G and CRLF2 overexpression and what is the connection with trisomy 21 in Down Syndrome?
3. Can Jak2 inhibitors have an effect on B cell lymphoproliferative disease or ALL with JAK2-R683G mutation?
We will address these questions by characterizing the JAK2-R683G transgenic mouse model and comparing it with the JAK2 transgenic models for JAK2-V617F and JAK2 exon 12 that we have generated. We will test the synergism between mutated JAK2-R683G an additional genetic events by overexpressing CRLF2 by retroviral transduction or by crossing our mice with mouse models of Down Syndrome. We have established a system to test the effects of Jak2 inhibitors in our transgenic mice and this system will also allow us to examine whether Jak2 inhibitors exhibit selectivity for the mutated Jak2 proteins.
These experiments should advance our understanding of the pathogenesis of ALL in children with Down syndrome and may provide a pre-clinical model to test new therapeutic approaches. |
| Financed by |
Foundations and Associations
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10/05/2024
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