Bone marrow mesenchymal stromal cells in chronic myelomonocytic leukaemia: overactivated WNT/beta-catenin signalling by parallel RNA sequencing and dysfunctional phenotypes

摘要

Sophisticated cross-talk between bone marrow mesenchymal stromal cells (BM MSCs) and haematopoietic/leukaemic stem cells in patients with myelodysplastic syndromes (MDS) and myeloid leukaemia have been emphasized in previous reports. However, mesenchymal elements in patients with chronic myelomonocytic leukaemia (CMML) were poorly investigated. By utilizing a parallel RNA-sequencing method, we investigated the transcriptional profile and functional defects of primary BM MSCs from patients with CMML for the first time. Within a 24-patient cohort, transcriptional and functional analysis reveals a prominent enrichment of WNT/beta-catenin signalling and multiple biology processes. Deregulated expression of WNT/beta-catnin factors CTNNB1, CMYC, LEF1, and FRZB is associated with impaired proliferation, senescence phenotype, and abnormal secretion in CMML MSCs. The impaired ability to support healthy CD34(+) haematopoietic stem and progenitor cells (HSPCs) correlates with activation of WNT/beta-catenin signalling in CMML MSCs. Furthermore, we observed an association between WNT/beta-catenin factors and treatment response to hypomethylating agents (HMAs) in a cohort of patients with MDS/myeloproliferative neoplasms (MPNs). Taken together, our study provides evidence for transcriptional and functional abnormalities in CMML MSCs, and suggests potential prognostic value of evaluating WNT/beta-catenin signalling in patients with CMML.