Loss of Asxl1 and Ezh2 cooperates in pathogenesis of haematological malignancies

: a potential mouse model for CLL pre-clinical study

Abstract

Loss-of-function mutations of ASXL1 or/and EZH2 are frequently found in patients with myeloid neoplasms, and their co-occurrence tends to result in more prognostically detrimental outcomes. While single knockout of Ezh2 in haematopoietic cells led to development of mild myelodysplastic disorders in the mouse model, double knockout of Asxl1 and Ezh2 further provided myeloproliferative features and promoted disease progress, resulting in a severe myelodysplastic/myeloproliferative neoplasm (MDS/MPN) phenotype. Intriguingly, in addition to myeloid malignancies, B-cell lymphoproliferative disorders (B-LPD) were also identified in Ezh2 cKO mice, and genetic co-inactivation of Asxl1 with Ezh2 enhanced the mono-clonal expansion and bone marrow infiltration of B1α cells, which ultimately progressed to an aggressive chronic lymphocytic leukaemia (CLL) phenotype with short latency and high-risk symptoms in secondary and tertiary transplantation. Meanwhile, while RNA-seq profiling revealed that active B cell receptor (BCR) signalling was crucial for the development of B-cell malignancies in Ezh2 single mutants, more critical genes involved in leukaemogenesis of CLL such as BCL-2, Myc, Cxcr5 and Aicda were further upregulated in Asxl1/Ezh2 double mutants, accounting for their aggressive properties of high cell division and organ infiltration. Furthermore, genetic and pharmacological inhibition of Ezh2 enhanced the anti-cancer effects of PARP inhibitors in acute myeloid leukaemia (AML) cells in vitro, providing a new strategy for improving the efficacy of PARP inhibitors in cancer therapy. Meanwhile, the transcriptional profiling displayed active BCR signalosome, base excision repair (BER) and Aicda overexpression in Asxl1/Ezh2 cKO CLL mice, further implying BTK and PARP1 as potential targets for the PRC2-deficient CLL. In vivo, while ibrutinib slightly delayed the disease latency with relief of cytopenia, the PARP inhibitor olaparib significantly prolonged the survival of Asxl1/Ezh2 cKO CLL mice and alleviated splenomegaly, showing therapeutic promises of targeting PARP1 for the treatment of human CLL with loss of PRC2 or the correlated transcriptional profiling.

Date of Award	1 Jun 2020
Original language	English
Awarding Institution	King's College London
Supervisor	Eric So (Supervisor)