BONE-MARROW STROMAL CELL DEFECTS AND 1-ALPHA,25-DIHYDROXYVITAMIN D-3 DEFICIENCY UNDERLYING HUMAN MYELOID LEUKEMIAS

Primary myelodysplasia (MDP) and acute and chronic myelogenous leukemi as (AML, CML) are considered disorders of clonal stem cell division. S everal constitutive gene defects that contribute to the development of abnormal cell behavior have been identified in the hematopoietic eels . The role of bone marrow stroma cells in leukemogenesis, however, has not been established. We studied the organization of the bone marrow (BM) microenvironment to see if it was impaired during the initiation and progression of these malignancies, The buffy coat, hematon, and pl asma fractions were separated from BM aspirates taken from healthy don ors and diseased subjects at distinct clinical stages. The structural integrity of the BM microenvironment was evaluated analyzing the morph ogenetic unit, the hematon. The hematon is a multicellular complex tha t includes fibroblasts, adipocytes, endothelial cells, resident macrop hages, hematopoietic cobblestone area-forming cells (CAFC), high-proli ferative potential colony-forming cells (HPP-CFC), granulocyte-macroph age colony-forming unit (GM-CFU), burst-forming unit erythroid (BFU-E) , and terminally differentiated cells in normal BM. Hematon complexes were present in most BM aspirates from healthy donors (46H(+)/55). But they were absent from most of the patients with MDP (21H(+)/62) and A ML (5H(+)/24) in the first perceptible phase, and from those with CML throughout the disease (5H(+)/55). Hematon complexes were present in t he BM aspirate in 22/36 AML patients at clinical remission after chemo therapy or differentiation therapy. The hematon fraction isolated from normal BM, contained 25 times more 25-hydroxyvitamin D-3 and about 50 0-fold more 1 alpha,25-dihydroxyvitamin D-3 than the BM plasma. The co ncentration of 1 alpha,25-dihydroxyvitamin D, was low or undetectable in the BM plasma of some, but not all, patients with MDP (18/35) or AM L (9/24). Thus, in the BM microenvironment, the metabolism of low-dens ity lipids and lipophylic hormones are severely impaired prior to init iation or during the accelerated expansion of leukemia cells. The lack of organized stromal network and the decreased level of some lipophyl ic hormones, acting probably as morphogens, may contribute to the onse t and progression of human myeloid leukemias.