Functional Modeling of Genes Upregulated in Chronic Myeloid Leukemia
Abstract: Chronic myeloid leukemia (CML) is caused by the transformation of a primitive hematopoietic cell by the BCR/ABL1 fusion gene that is formed through the chromosomal translocation t(9;22). CML is currently successfully treated with tyrosine kinase inhibitors targeting the ABL1 kinase domain. However, the CML stem cells are insensitive to this drug and a large fraction of patients will have relapse following discontinuation of the drug. Thus, improved therapeutic strategies are needed towards the ultimate goal of curing CML. In Article I, the functional role of supressor of cytokine signaling 2 (SOCS2) in CML and in normal hematopoiesis was investigated. Mice deficient for the Socs2 gene displayed normal steady-state hematopoiesis and hematopoietic stem cell (HSC) function. Transduction of bone marrow (BM) cells from Socs2-deficient mice with BCR/ABL1 and subsequent transplantation resulted in a CML-like disease indistuingishable from the disease in control mice, suggesting that SOCS2 is dispensible for normal hematopoiesis and CML pathogenesis. In Article II, global gene expression analysis and subsequent flow cytometric analysis of normal and CML BM cells showed that interleukin-1 receptor acessory protein (IL1RAP) was highly upregulated on the cell surface of CML cells, allowing prospective separation of candidate CML stem cells from normal hematopoietic stem cells. The use of a polyclonal IL1RAP antibody enabled antibody-dependent cellular cytotoxicity (ADCC) of CD34+CD38- CML cells in vitro. In Article III, the function of IL1RAP in normal hematopoeisis and in CML was investigated. Mice lacking Il1rap displayed lower myeloid steady-state cell counts. Overexpression of IL1RAP in cord blood cells, followed by transplantation into immunodeficient mice, resulted in increased levels of myelopoeisis. Finally, CD34+CD38- CML cells were found to respond strongly to IL1B stimulation in vitro. Together, the results suggest that IL1RAP is a promising target for novel therapeutic approaches in CML.
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