Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence.

Primary myelofibrosis (PMF) is the rarest and the most severe Philadelphia-negative chronic myeloproliferative syndrome. By associating a clonal proliferation and a mobilization of hematopoietic stem cells from bone marrow to spleen with profound alterations of the stroma, PMF is a remarkable model in which deregulation of the stem cell niche is of utmost importance for the disease development. This paper reviews key data suggesting that an imbalance between endosteal and vascular niches participates in the development of clonal stem cell proliferation. Mechanisms by which bone marrow niches are altered with ensuing mobilization and homing of neoplastic hematopoietic stem cells in new or reinitialized niches in the spleen and liver are examined. Differences between signals delivered by both endosteal and vascular niches in the bone marrow and spleen of patients as well as the responsiveness of PMF stem cells to their specific signals are discussed. A proposal for integrating a potential role for the JAK2 mutation in their altered sensitivity is made. A better understanding of the cross talk between stem cells and their niche should imply new therapeutic strategies targeting not only intrinsic defects in stem cell signaling but also regulatory hematopoietic niche-derived signals and, consequently, stem cell proliferation.

Cellular and molecular mechanisms underlying bone marrow and liver fibrosis: a review.

Chronic fibroproliferative diseases are an important cause of morbidity and mortality in the world. Fibrotic diseases occur in a large variety of vital organs, and the process of fibrosis seems common to all tissues. In all of fibrotic reactions, the underlying cellular and molecular mechanisms involve leukocyte infiltration, the persistence of inflammation in the tissue, and the proliferation of cells with a myofibroblast phenotype. The different cell types participating to this process sustain production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines, which together stimulate the deposition of connective tissue elements that progressively destroy and remodel normal tissue architecture. This review focuses on the comparison of two, major, chronic fibroproliferative diseases: the myelofibrosis which develops in bone marrow, a "fluid" tissue producing circulating haematopoietic cells, and liver fibrosis, which demonstrates all the features of solid tissue damage. We discuss the etiology and histological quantification of each type of fibrosis, the implication of cell partners, cytokines and growth factors, animal models developed to study fibrosis, and antifibrotic therapies for each of these two fibroproliferative disease models.

Stem cell dysregulation in myelofibrosis with myeloid metaplasia: current data on growth factor and transcription factor involvement.

Myelofibrosis with myeloid metaplasia (MMM), the rarest Philadelphia chromosome-negative chronic myeloproliferative disorder (MPD), is characterized by extramedullary hematopoiesis and myelofibrosis. The primary molecular defect leading to the clonal amplification of the hematopoietic progenitors is still unknown. In this review, we will focus on current data in favor of a pivotal role for hematopoietic and fibrogenic growth factors and of transcription factors in the dysregulation of the hematopoietic compartment. These data shed novel insight into the genesis of MMM myeloproliferation and led us to propose a model, integrating alterations in the expression and function of nuclear regulatory factors and in the hierarchical and complex network of interactions between hematopoietic cells and stroma in the pathogenetic mechanisms of the disease.

Critical review of pathogenetic mechanisms in myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia is an uncommon chronic myeloproliferative disorder characterized by extramedullary hematopoiesis associated with varying degrees of bone marrow fibrosis (hematopoiesis is clonal and fibrosis is a polyclonal reactive process). The primary defect in a pluripotent stem cell is still unknown. However, advances have been made during the past few years in the knowledge of the pathogenetic mechanisms in this disorder. This review focuses on current data on the cellular and molecular mechanisms possibly participating in the development of the disease.