Abstract
Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2Val617F mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.
Highlights
Philadelphia-negative chronic myeloproliferative neoplams (Ph- Philadelphia-negative chronic MyeloProliferative Neoplasms (MPNs)) are clonal hemopathies that arise from the oncogenic transformation of hematopoietic stem/progenitor cells that conserve full differentiation potential with qualitative and quantitative abnormalities [1]
In contrast to chronic myeloid leukaemia, the molecular mechanisms leading to Ph- MPN progression have remained unclear until the recent finding of the V617F JAK2 mutation in most of Polycythemia Vera (PV) and half of Essential Thrombocytosis (ET) and Primary Myelofibrosis (PMF) cases ([3], see for review [4])
Conclusion and perspectives by combining a clonal proliferation and a mobilization of hematopoietic stem cell(s) with marked alterations of the bone marrow and spleen stroma, PMF illustrates a unique model in which a “hematopoietic stem cell niche” deregulation plays a key role in the myeloproliferative process
Summary
Besides the potential role of altered growth factor signaling pathways, a number of converging arguments suggests that changes within the hematopoietic environment take part in MPN pathogenesis. The stromal reaction It is accepted that myelofibrosis associating the clonal myeloproliferation is a multifactor process resulting from alterations of fibroblasts leading to the modified expression of adhesion molecules and to an increased deposit of extracellular matrix components [30] This accumulation is suggested to be the consequence of intramedullary release of growth factors by the malignant hematopoietic clone and especially by dysplastic megakaryocytes [31]. Such disequilibrium would favor the proliferation and mobilization of pathological stem cells including hematopoietic, mesenchymal and endothelial stem/progenitor cells from the bone marrow to the blood, leading to bone marrow aplasia and stem cell mobilization These stem cells would migrate into the spleen where newly created or reinitialized vascular niches would favor their homing and abnormal differentiation resulting in an extramedullary hematopoiesis at Figure 4 PMF; the “Bad Seeds in Bad Soil” model. Till the absence of recurrent genomic abnormalities in PMF patients does not allow us to definitively conclude on this challenging concern
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