The distinct patterns of bone marrow involvement by non-Hodgkin’s lymphomas provide the best visual illustration of the existence of spatially defined microenvironments in the bone–bone

marrow organ, sought by distinct populations of cancer cells. Follicular lymphoma grows as paratrabecular nodules, whereas marginal click here zone lymphomas and other types (hairy cell leukemia, mantle cell lymphoma) characteristically infiltrate sinusoids. Tumor-specific patterns of adhesion molecule expression may underpin such specific tropism for distinct microanatomical sites, the specific stromal composition of which remains to be elucidated. The myelofibrosis and osteosclerosis seen in myeloproliferative neoplasms (MPNs), in turn, represent the best visual demonstration of the involvement of stromal osteoprogenitors in the profound changes occurring in

the hematopoietic microenvironment and niche in MPNs. Notably, the appearance of intravascular and extramedullary hematopoiesis in primary myelofibrosis may be linked to a profound subversion of Gefitinib molecular weight the CXCL12/CXCR4 axis, which normally directs homing of HSCs to the marrow extravascular environment [66]. Human [2] and murine [8] and [67] perivascular osteoprogenitors are the prime source of CXCL12 in the perivascular/extravascular environment in bone marrow; stromal osteoprogenitors increase in number in primary myelofibrosis (PMF) [68], but local availability of CXCL12 is decreased due to enhanced clearance and proteolytic degradation, and expression of CXCR4

in HSCs may be decreased [69] and [70]. A host of interactions between myeloid cancer cells and stromal progenitors have been described, highlighting a complex bidirectional interplay involving a variety of pathways such as Wnt and adhesion molecule-conveyed signals [71]. Here too, the role of stromal-derived CXCL12 is pivotal in a number of key events [72] Changes in the function of stromal progenitors ALOX15 induced by cancer cells in turn result in tissue changes such as fibrosis and perturbation of niche/microenvironment effects on normal hematopoiesis [73] and [74]. Likewise, hematopoietic cancer may alter the function of additional cell types that may normally contribute to a functional “niche”/HME effect, ultimately resulting in promotion of cancer growth [15]. No doubt, the most intriguing findings are those suggesting a primary role of osteoprogenitors in directing the leukemogenic process itself. These include the observation of genetic changes in stromal cells in patients with myelodysplasia [75] and [76], mouse models of myeloproliferative neoplasia secondary to genetic changes in the stroma [77], and induction of myelodysplasia and leukemia in mice as a result of Dicer-1 knockout in osteoprogenitors proper [9]. These data illustrate at the same time a specific “niche” (as opposed to microenvironment) effect as a function of osteoprogenitors proper.