DEVELOPMENT OF AN ANIMAL MODEL TO STUDY THE ROLE OF THE PHOSPHATASE PTPN22 IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIAÖznur Özlem Ibrahimoğlu
, 2016, doctoral dissertation
Abstract: A polymorphic variant of the phosphatase PTPN22 has recently emerged as a major risk factor for the development of multiple autoimmune diseases. The mechanism how this variant increases the susceptibility for autoimmune diseases is still unclear. A recent study by our lab showed that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), which is a common lymphoid malignancy characterized by the clonal outgrowth of autoreactive B lymphocytes. This study also showed that PTPN22 functions primarily as a negative regulator of B cell receptor (BCR) signaling, but can also positively affect the activity of certain downstream signaling pathways.
To understand the role of PTPN22 in the pathogenesis of CLL, we investigated PTPN22 expression in leukemias that develop in the Eµ-TCL1 transgenic mouse model. We observed that PTPN22 is highly overexpressed in these leukemias. We also evaluated expression of PTPN22 in normal murine B cell subsets corresponding to different stages of B cell development and differentiation. We detected high PTPN22 expression in B1 B cells, which are the normal counterparts of CLL B cells, and lower levels in marginal zone B cells, whereas PTPN22 was not expressed or was expressed at extremely low levels in most of the other investigated B cell subsets.We generated knockout mice with targeted disruption of PTPN22. We showed that PTPN22 is not expressed by any B cell subset in PTPN22-/- mice, including B1 B cells. To investigate the impact of PTPN22 deficiency on B1 and marginal zone B cell development and function, we performed immunophenotyping analysis of bone marrow, spleen and peritoneal cavity B cells from a large series of PTPN22-/- and age-matched wild type mice. A small but appreciable reduction in the percentage of marginal zone B cells and an increase in the percentage of B1 B cells in older PTPN22-/- mice was observed. These changes were consistent with the increased levels of natural antibodies typically produced by B1 B cells and lower levels of antibodies typically produced by marginal zone B cells in PTPN22 deficient mice. Altogether, these data suggest that PTPN22 deficiency results in reduced marginal zone and increased B1 B cell immune responses. Importantly, this phenotype is remarkably similar to the phenotype of SHP1-/- mice, although considerably milder. Since SHP1 is the main negative regulator of proximal BCR signaling in B cells, these findings suggest that one important function of PTPN22 could be to provide additional fine-tuning of the intensity of the BCR signal in B1 and marginal zone B cells. In support of this possibility, a modest but consistent increase in anti-IgM-induced calcium mobilization was observed in B1 B cells from PTPN22-deficient compared to wild type mice.To see how PTPN22 deficiency will affect leukemia development and behavior, we crossed PTPN22 knockout mice with E-TCL1 transgenic mice. PTPN22 deficiency accelerated the expansion of the malignant B cells in this model and resulted in earlier leukemia development in comparison to wild type E-TCL1 transgenic mice. These data are consistent with other recent studies from our group showing that a greater capacity to activate downstream signaling pathways upon engagement of the BCR with external ligand is associated with more rapid disease progression in both human CLL and the E-TCL1 model.
In conclusion, we show that PTPN22 is equally overexpressed in normal and leukemic B1 B cells derived from E-TCL1 transgenic mice, suggesting that PTPN22 overexpression is not due to the transforming event, at least in the case of murine CLL. The greater BCR signaling capacity of B1 B cells and the accelerated leukemia development in PTPN22-deficient mice further argues for an important role of BCR signals in determining the aggressiveness of CLL.
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Keywords: PTPN22, BCR signalling, B1 B cells, marginal zone B cells, chronic lymphocytic leukemia (CLL), autoimmunity.
Published: 31.01.2017; Views: 2669; Downloads: 187
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