To determine whether the erythropoietin (epo) insensitivity of erythroid progenitor differentiation in congenital pure red cell aplasia or Diamond-Blackfan anaemia is intrinsic to the progenitor itself or is due to defective accessory cell function or active suppression, progenitors from normals and two patients (one steroid resistant and one spontaneously remitting), separated from all known accessory cells using sequential negative selection techniques (adherence, E-rosetting, and direct and indirect immune-panning), were studied. Initially, we evaluated three patients with DBA using unfractionated bone marrow mononuclear cells. Progenitors from two steroid non-responsive patients showed insensitivity to crude epo (c-epo) while one steroid responsive patient demonstrated normal in vitro sensitivity to c-epo. When recombinant epo (r-epo) was used in place of c-epo, the two steroid non-responders continued to demonstrate in vitro progenitor epo insensitivity. However, sensitivity of progenitors from the steroid responder, which was normal in the presence of c-epo, became abnormal when recombinant epo (r-epo) was substituted. Thus, using unfractionated bone marrow, the abnormal response to epo of progenitors from some patients with DBA appears to be obscured by stimulating factors termed erythroid burst-promoting activity (BPA) which are present in c-epo. Using fractionated highly enriched progenitors, from normals and a steroid responsive patient a final 3-10-fold enrichment of progenitors was achieved, but no such enrichment was seen when marrow from a steroid resistant patient was cultured. The epo sensitivities of normal and of patient erythroid progenitors were similar. However, at sub-optimal epo concentrations in both patients CFU-E responsiveness to crude BPA was abnormal compared to the three controls. We conclude from these studies that in DBA: (a) the failure of erythropoiesis is due to an intrinsic progenitor defect; (b) this defect involves progenitor insensitivity to factors in addition to erythropoietin: and (c) there exists a spectrum of disease reflected in the degree of the in vitro abnormality observed.

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ABSTRACT. Gaucher disease is the most prevalent lysoGaucher disease is the most prevalent lysosomal storage disease soma1 storage disease. This autosomal recessive disease is (I) and the most frequent genetic disease in the Ashkenazi Jewish caused by the defective activity of the enzyme acid 8-population (2). This autosomal recessive disorder of glycosphinglucosidase and the resultant accumulation of glucosylcer-golipid metabolism results from numerous point mutations at amide primarily within cells of the reticuloendothelial SyS-the locus-encoding acid (3-glucosidase (glucocerebrosidase) (for tern. Because the primary manifestations of Gaucher review, see Ref. 3). The majority of these are missense mutations, disease are due to involvement of mono~yte/macro~hage-which lead to the defective activity of this enzyme (3-5). The derived this disease is be an resultant accumulation of the substrate, glucosylceramide, within candidate for curative intervention via bone marrow trans-m o n o c y t e~m a c r o p~a g e -~e~v e~ cells (~~~ cells) leads to the ~lantation (BMT). A is panic female with subacute neu-visceral manifestations including hepatosplenomegaly, hyperronopathic Gaucher disease and progressing splenism, and skeletal disease (6). Three variants of the disease manifestations underwent BMT at 23 m0 of age using have been delineated based on the absence (type 1, nonneuronher brother as the donor' Cytoge-opathic) or presence (neuronopathic) and severity (type 2, acute; netic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, type 3 subacute) of primary CNS involvement (6). Because the biochemical, enzymatic, and histologic studies demon-major visceral manifestations of this disease result from the strated nearly complete correction in the viscera. H~~ accumulation of bone marrow-derived tissue-bound macroneuropathic manifestations did not progress. Complete re-phages, Gaucher disease type 1 has been a prime candidate for constitution of enzymatic activity in peripheral blood leu-curative intervention by BMT. In addition, demonstration of the kocytes was achieved by 1 mo. Cytogenetic analyses dem-clinical, biochemical, and histopathologic efficacy of BMT would onstrated complete engraftment by d 79 and nearly corn-provide the basis for ongoing efforts directed toward molecular plete loss of bone marrow Gaucher cells was observed by therapy for this disease.

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