Bone Marrow Remodelling and Topographic Redistribution of CD34 Positive Progenitors Characterize the Progression of Myelodysplastic Syndromes and Their Evolution to AML

Myelodysplastic Syndrome (MDS) is a multifaceted disease of Hematopoietic Stem Cells characterized by myeloproliferation associated with mono- or pan-cytopenia, ultimately leading to an advantageous clonal growth of frankly leukemic cells. Although the disruption of bone marrow (BM) architecture and alterations of differentiated hematopoietic compartments have been repeatedly described, the potential involvement of the structural remodeling and redistribution of hematopoietic progenitors within the BM on the evolution of MDS has been poorly investigated. The aim of our study was to determine whether the number and localization of CD34^pos progenitors and vascular structures are differentially affected in MDS subcategories and whether these changes are associated with disease progression. Thus, the morphometric evaluation of the number and linear distance from the endosteal surface (PT: paratrabecular <20mm; IT: intertrabecular >21mm) of capillaries, sinusoids, arterioles and CD34^pos progenitors was performed by immunohistochemistry on BM biopsies from 97 consecutive MDS patients (12 RA; 2 RCUD; 19 RCMD; 3 RARS-T; 2 5q-; 20 RAEB-1; 27 RAEB-2; 12 U-MDS) in stable or evolving disease and in 15 cases that progressed to AML. Controls (CTR) were represented by 22 disease-free BM biopsies. Risk stratification was based on IPSS. Compared to CTR, capillary density linearly increased in IT marrow from RA thorough RAEB-1, with a subsequent progressive drop in RAEB-2 and AML. Sinusoid density was reduced in MDS and progressively declined from RAEB-1 through AML. PT and IT arterioles increased by more than 3-fold in MDS vs CTR although a progressive rarefaction associated with an increased thickness was measured from RA thorough RAEB-2. A marked rise in arteriolar number was also observed in AML. As expected, CD34^pos cell number progressively increased with the severity of the disease, however, a sharp redistribution from PT to perisinusoid and fat areas within the IT marrow was documented (Figure). Intriguingly, the BM redistribution of vascular structures had higher impact than the increased number of CD34^pos progenitors to identify high risk MDS and the subset of MDS patients who subsequently developed AML. Finally, patients responsive to azacytidine displayed a reduced number and a topographic redistribution of CD34^pos cells together with an increased BM capillarization. BM structural remodelling and rearrangement of hematopoietic progenitors characterize the evolution of MDS. The prognostic significance and the predictive value of these parameters may be translated in new therapeutic approaches able to improve patient management.

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