Hind Medyouf

Myelodysplastic Cells in Patients Reprogram Mesenchymal Stromal Cells to Establish a Transplantable Stem Cell Niche Disease Unit

Myelodysplastic syndromes (MDSs) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem and progenitor cells (HSPCs) and possibly the HSPC niche. Here, we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating Lin(-)CD34(+)CD38(-) stem cells in orthotopic xenografts. Overproduction of niche factors such as CDH2 (N-Cadherin), IGFBP2, VEGFA, and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets in order to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt MDS MSC-like molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of the microenvironment. Therefore, this patient-derived xenograft model provides functional and molecular evidence that MDS is a complex disease that involves both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.

Myelodysplasia is in the niche: novel concepts and emerging therapies.

Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of ‘osteohematology’ as an emerging research field in MDS and outline clinical implications.

Loss of SPARC protects hematopoietic stem cells from chemotherapy toxicity by accelerating their return to quiescence

Around birth, hematopoietic stem cells (HSCs) expanding in the fetal liver migrate to the developing bone marrow (BM) to mature and expand. To identify the molecular processes associated with HSCs located in the 2 different microenvironments, we compared the expression profiles of HSCs present in the liver and BM of perinatal mice. This revealed the higher expression of a cluster of extracellular matrix-related genes in BM HSCs, with secreted protein acidic and rich in cysteine (SPARC) being one of the most significant ones. This extracellular matrix protein has been described to be involved in tissue development, repair, and remodeling, as well as metastasis formation. Here we demonstrate that SPARC-deficient mice display higher resistance to serial treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). Using straight and reverse chimeras, we further show that this protective effect is not due to a role of SPARC in HSCs, but rather is due to its function in the BM niche. Although the kinetics of recovery of the hematopoietic system is normal, HSCs in a SPARC-deficient niche show an accelerated return to quiescence, protecting them from the lethal effects of serial 5-FU treatment. This may become clinically relevant, as SPARC inhibition and its protective effect on HSCs could be used to optimize chemotherapy schemes.

MiR144/451 expression is repressed by RUNX1 during megakaryopoiesis and disturbed by RUNX1/ETO

A network of lineage-specific transcription factors and microRNAs tightly regulates differentiation of hematopoietic stem cells along the distinct lineages. Deregulation of this regulatory network contributes to impaired lineage fidelity and leukemogenesis. We found that the hematopoietic master regulator RUNX1 controls the expression of certain microRNAs, of importance during erythroid/megakaryocytic differentiation. In particular, we show that the erythorid miR144/451 cluster is epigenetically repressed by RUNX1 during megakaryopoiesis. Furthermore, the leukemogenic RUNX1/ETO fusion protein transcriptionally represses the miR144/451 pre-microRNA. Thus RUNX1/ETO contributes to increased expression of miR451 target genes and interferes with normal gene expression during differentiation. Furthermore, we observed that inhibition of RUNX1/ETO in Kasumi1 cells and in RUNX1/ETO positive primary acute myeloid leukemia patient samples leads to up-regulation of miR144/451. RUNX1 thus emerges as a key regulator of a microRNA network, driving differentiation at the megakaryocytic/erythroid branching point. The network is disturbed by the leukemogenic RUNX1/ETO fusion product.

Suppression of RUNX1/ETO oncogenic activity by a small molecule inhibitor of tetramerization

RUNX1/ETO, the product of the t(8;21) chromosomal translocation, is required for the onset and maintenance of one of the most common forms of acute myeloid leukemia (AML). RUNX1/ETO has a modular structure and, besides the DNA-binding domain (Runt), contains four evolutionary conserved functional domains named nervy homology regions 1-4 (NHR1 to NHR4). The NHR domains serve as docking sites for a variety of different proteins and, in addition, the NHR2 domain mediates tetramerization through hydrophobic and ionic/polar interactions. Tetramerization is essential for RUNX1/ETO oncogenic activity. Destabilization of the RUNX1/ETO high molecular weight complex abrogates RUNX1/ETO oncogenic activity. Using structure-based virtual screening, we identified several small molecule inhibitors mimicking the tetramerization hot spot within

Clonal hierarchies and dynamic evolution in Myelodysplastic Syndromes (MDS) upon therapy

T cell stimulation with different cytokines results in distinct phenotypes and cytotoxic activity of CD19-specific CART cells