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Zhiyan Xu

DPhil Student

Myeloproliferative neoplasms (MPN) are a group of haematologic diseases characterized by abnormal proliferation of blood cells in the bone marrow and terminal expansion of myeloid cells in the peripheral blood. MPN are divided into 2 subgroups depending on the presence or absence of the ‘Philadelphia (Ph) chromosome’ - t(9;22)(q34.1;q11.2), i.e., the BCR-ABL1 translocation. BCR-ABL1+ MPN is chronic myeloid leukaemia (CML), characterized by uncontrolled production of granulocytes. Tyrosine kinase inhibitors (TKIs) are recommended as first-line or second-line treatment. But among a small proportion of CML cases, resistance to TKIs develops and progression to blast phase (BP) occurs.

Many studies have investigated mechanisms underlying drug resistance. Primary resistance is insensitivity and lack of response to treatment. Secondary resistance is acquired during treatment. This primary resistance of insensitivity to treatment attributes to a small subset of quiescent CML leukemia stem cells (LSCs). The persistence of quiescent CML-LSCs constitutes a reservoir that underlies the disease recurrence in case of treatment discontinuation.  

The overarching aim of my project is to find and validate a novel target for TKI-insensitive CML-LSCs. First, an efficient and optimized gene manipulation strategy needs to be established. Second, the gene knock-out effect will be studied in-vitro and in-vivo with PDX models. Target gene-involved pathways in regulating CML LSCs will be investigated further.