Advanced Stage Primary Myelofibrosis Is Characterized by Loss of Marrow Hematopoietic Stem Cells Associated with Alterations of the Stem Cell Niche
M Arabadjief, JT Geyer, S Barouk, DM Knowles, I Ouansafi, R Hoffman, A Orazi. Weill Cornell Medical College, New York; Mount Sinai School of Medicine, New York
Background: Interactions of hematopoietic stem cells (HSC) with the stroma/microenvironment inside bone cavities are central to hematopoiesis as they regulate cell proliferation, self-renewal and differentiation. HSC niches are specialized microenvironments that contain HSC and regulate their maintenance. The niches are mainly periendosteal in location, at least in animal models. Primary myelofibrosis (PMF) is a hematopoietic neoplasm which is thought to be associated with abnormalities of the HSC niche. Thus, architectural alteration of the stem cell niche may be of importance for the disease development. To investigate this phenomenon, we compared normal controls to patients with PMF, the latter divided into early fibrotic (MF-1) and fibrotic (MF-2/3) groups according to the European Consensus System for assessing marrow fibrosis.
Design: The frequency and distribution of CD34+ cells in the bone marrow (BM) of patients with PMF were determined using CD34 immunostaining. The evaluation was performed by assessing the number of CD34+ cells per 2 mm² by using an ocular micrometer. To assess for architectural alterations in the periendosteal areas, which may translate into loss of HSC niches, osteoblasts were immunostained with CD56. Osteoclasts were identified by CD68 (KP1) immunostaining.
Results: Seven patients with early PMF (MF-1), 22 patients with advanced PMF (MF-2/3), and 13 control adult BM biopsy samples were studied. In comparison with control marrows (mean CD34+ cells: 6.15±4.2), patients with MF-2/3 revealed a significantly decreased number of CD34+ cells (mean 2.07±2.9; P<0.05). MF-1 showed lower values (mean CD34+ cells: 4.9±3.8) than the control marrows, although the difference was not significant. All cases of advanced PMF showed profound stromal alterations as well as abnormalities in the distribution of CD68+ osteoclasts and CD56+ osteoblasts.
Conclusions: Enhanced egress of hematopoietic precursors from the BM with subsequent trapping by the spleen and other extramedullary sites as seen in advanced stage PMF (MF-2/3) is significantly associated with a measurable decrease in the frequency of BM CD34+ cells. This is most likely a consequence of loss of the normal HSC niches, as suggested by the abnormalities documented in the periendosteal areas, with subsequent migration of these cells to perivascular/ endovascular locations prior to their bone marrow egression.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 175, Monday Morning