Primary myelofibrosis and the "bad seeds in bad soil" concept

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 JAK2(Val617F) 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.

Figure 1

Pathophysiological characteristics of PMF. Primary myelofibrosis is characterized by a clonal amplification of hematopoietic stem cells (HSCs) and a prominent proliferation of "dystrophic" megakaryocytes (MK) that partly result from the presence of gain-of-function mutations involving JAK2 and MPL genes and that is associated with a migration of HSC from bone marrow (BM) to spleen and liver through peripheral blood (PB). Such myeloproliferation is associated with alterations of stroma featured by a myelofibrosis, an osteosclerosis and a neoangiogenesis. This stromal reaction is reported to be secondary to the stimulation of stromal cells including fibroblasts, osteoblasts and endothelial cells by growth factors (GFs) produced in excess by cells from the hematopoietic clone and especially by MK cells.

Figure 2

Schematic representation of the medullar niches. In healthy adults, hematopoiesis occurs in the bone marrow where hematopoietic stem cells (HSCs) are engaged in a constant crosstalk within specific niches. Very schematically, these haematopoietic stem cell niches are conceptually divided into two niches: The endosteal niche in which osteoblasts, derived from Mesenchymal Stromal Cell (MSC) differentiation and contributing to bone formation and osteoclats, derived from HSCs, and participating in bone resorption played a crucial role. The vascular niche in which endothelial cells, resulting from the proliferation and differentiation of Endothelial Stem Cells (ESC), are in close contact with HSC within the perivascular spaces. Beyond cell-cell contacts through receptor-ligand and adhesion molecule interactions, extracellular matrix component (EMC), cytokines and chemokines, proteases, calcium and oxygen concentrations are essential environmental components of these niches.

Figure 3

Role of growth factors in PMF stromal reaction. In PMF, myelofibrosis is a multifactor process resulting from alterations of fibroblasts/MSC leading to an increased deposit of extracellular matrix components resulting from growth factors released by malignant hematopoietic cells and especially MK and monocytes. These growth factors would further activate stromal cells, leading to myelofibrosis, osteosclerosis and neoangiogenesis.

Figure 4

PMF; the "Bad Seeds in Bad Soil" model. In PMF, whereas the initial molecular defect at the origin of the hematopoietic clone is still unknown, altered interactions between CD34⁺ HSCs and stromal cells in the medullar environment would result in an increased cytokine production by the clonal hematopoietic cells and especially by dystrophic megakaryocytes and monocytes. Production in excess of hematopoietic, fibrogenic, and angiogenic growth factors would stimulate myelofibrosis, osteosclerosis and angiogenesis through activation of stromal and endothelial cells. Consequently, by acquiring new properties, stromal cells would create a pathological microenvironment that participates in the development and maintenance of the hematopoietic clone. Mk: Megakaryocytes; Mo: Monocytes; Ne: Neutrophiles; Ob: Osteoblasts; Oc: osteoclasts; Fb: Fibroblasts.

Figure 5

PMF stem cells moving from niches to niches. In response to several environmental factors, an imbalance between endosteal and vascular niches within the bone marrow would favor the proliferation and mobilization of pathological stem cells from the bone marrow to the blood. These stem cells would migrate into the spleen/liver where newly created or reinitialized vascular niches would favor their homing and differentiation resulting in an extramedullary hematopoiesis in these organs.