Tumor microenvironment and clonal monocytes from chronic myelomonocytic leukemia induce a procoagulant climate

Abstract

Chronic myelomonocytic leukemia (CMML) is a myeloid hematological malignancy with overlapping features of myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). The knowledge of the role of the tumor microenvironment (TME), particularly mesenchymal stromal cells (MSCs), in MDS pathogenesis is increasing. Generally, cancer is associated with a procoagulant state participating in tumor development. Monocytes release procoagulant, tissue factor (TF)–bearing microparticles. We hypothesized that MSCs and clonal monocytes release procoagulant extracellular vesicles (EVs) within the CMML TME, inducing a procoagulant state that could modify hematopoietic stem cell (HSC) homeostasis. We isolated and cultured MSCs and monocytes from CMML patients and MSCs from healthy donors (HDs). Their medium EVs and small EVs (sEVs) were collected after iterative ultracentrifugations and characterized by nanoparticle tracking analysis. Their impact on hemostasis was studied with a thrombin generation assay and fibrinography. CMML or HD HSCs were exposed to sEVs from either CMML or HD MSCs. CMML MSC sEVs increased HD HSC procoagulant activity, suggesting a transfer of TF from the CMML TME to HD HSCs. The presence of TF on sEVs was shown by electron microscopy and western blot. Moreover, CMML monocyte EVs conferred a procoagulant activity to HD MSCs, which was reversed by an anti-TF antibody, suggesting the presence of TF on the EVs. Our findings revealed a procoagulant “climate” within the CMML environment related to TF-bearing sEVs secreted by CMML MSCs and monocytes.

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

“…CMML has generally been exclusively considered as an HSPC events‐driven disease over the past decades. Recently, accumulating evidence has indicated that functional alterations in BM MSCs contribute to the development of myeloid malignancies 4,31,32 . Raaijmakers et al .…”

“…2 Recent experimental data have emphasized the participation of bone marrow mesenchymal elements in the pathogenesis of multiple myeloid malignancies, while studies on the bone marrow microenvironment in CMML are rare. 3,4 Generally, genetic perturbations of mesenchymal cells are sufficient to induce MDS/acute myeloid leukaemia (AML)-like phenotypes, which establish a concept of 'niche-induced' oncogenesis. 5,6 These studies challenged the concept that myeloid disorders are exclusively driven by autonomous events in haematopoietic cells.…”

The “Vesicular Intelligence” Strategy of Blood Cancers

“…Chronic myelomonocytic leukemia (CMML) is a myeloid hematological malignancy with overlapping characteristics of MDS and MPN. It has been reported that CMML monocyte EVs confer a procoagulant activity to healthy donor MSC, which can be reversed by an anti-TF antibody [ 136 ].…”

Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects

“…In chronic myeloid leukemia (CML), leukemia cells altered the cellular and immune-related properties of BM-MSCs and macrophages in vitro by the mean of exosomes ( Jafarzadeh et al, 2019 ). Consistently, Zannoni et al (2019) reported that EVs released by monocytes from chronic myelomonocytic leukemia patients conferred a procoagulant state favorable for cancer progression, through a tissue factor-dependent mechanism mediated by MSCs. In glioma, exosomes from cancer cells induced a tumor-like phenotype in MSCs by activating glycolysis ( Ma et al, 2019 ).…”