Characterisation of Immune Cell Subsets in Mouse Models of Myeloproliferative Neoplasms

Recent studies have implicated the role that the microenvironment plays in disease evolution. Changes in specific molecules can directly modulate haematopoietic stem cells (HSCs) to make different numbers and types of cells and this suggests that the microenvironment might mediate disease development. My thesis explores this in the context of myeloproliferative neoplasms, a set of clonal HSC-derived disorders that are considered pre-leukaemic. Specifically, I will assess the impact of CXCL10 (or IP-10) on HSPCs and mature cell production in an allelic series of models.
Studies have previously shown that notably higher levels of CXCL10 are associated with increased disease severity in both human patient studies and mouse models of MPNs. This has been demonstrated by serum cytokine profiling and correlation to disease severity in both patients and mice. In my thesis, I, therefore, explored the impact of CXCL10 loss on disease severity, using flow cytometry in mouse models with either JAK2 V617F mutations, TET2 mutations, or CXCL10 mutations (or combinations of these), Mice deficient in IP-10 show slower MPN disease development with reduced erythrocytosis. This work established that CXCL10 impacted the numbers and types of cells in the bone marrow. Next, I went on to validate genes expressed in these cell subsets by performing qRT-PCR, identifying a key regulator of disease.
Together, my findings highlight the importance of extrinsic cellular regulators and support the theory that changes in the haematopoietic microenvironment can alter cellular fate outcomes in the malignant setting, my work highlights the need to undertake future investigations to identify cellular and molecular pathways that might be targeted to improve patient outcomes.