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4114 Changes of the Niche of Erythropoiesis Appear to Contribute to Severe Transfusion-Dependent Anemia in a Significant Proportion of Patients with Myelodysplastic Syndromes

Myelodysplastic Syndromes – Basic and Translational Studies
Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes – Basic and Translational Studies: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Guntram Buesche, MD1, Aristoteles Giagounidis, MD, PhD2, Gudrun Göhring, M.D.3*, Brigitte Schlegelberger, MD, Prof.3, Arnold Ganser, M.D.4, Carlo Aul, MD5* and Hans Heinrich Kreipe, M.D.6*

1Department of Pathology, Hannover Medical School, Hannover, Germany
2Marien Hospital Düsseldorf, Düsseldorf, Germany
3Institute of Human Genetics, Hannover Medical School, Hannover, Germany
4Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
5Klinik für Onkologie und Hämatologie, HELIOS St. Johannes Klinik, Duisburg, Germany
6Institute of Pathology, Hannover Medical School, Hannover, Germany

Erythroid precursors proliferate and differentiate within a specialized niche, the erythroblastic island (Ery-I). Although this entity has been known for more than 50 years, its significance to anemia, the leading symptom of myelodysplastic syndromes (MDS), has not been clarified as yet. Bone marrow biopsies from a total of 356 patients with MDS, treated by best supportive care (n = 317) or with lenalidomide (n = 39), were evaluated for alterations of erythropoiesis and Ery-Is by combining immunophenotyping of erythropoietic cells with statistical analysis of their clustering and the results were compared to those from 52 persons with healthy marrow. Enlargement of Ery-Is was a typical feature of MDS as well as of aging healthy marrow (P<0.000005). In MDS, enlargement could be put down to increased numbers of immature erythroid cells. It occurred independently of other dysplastic features of erythropoiesis and did not contribute to anemia, but it was associated with increased numbers of apoptotic erythroid cells (P < 0.00001). In 72.6% of MDS patients, a dissociation of the central iron-presenting macrophages from >10% of Ery-Is was detected, a feature not observed in healthy marrow (P < 0.000005). The dissociation of the central (CD169+) macrophages from Ery-Is was associated with an impaired formation, a disruption, or a loss of a significant proportion of Ery-Is in 45.7% of patients, a feature not observed in healthy marrow (P < 0.000005). Impaired formation, disruption, or loss of Ery-Is turned out to be the most important unfavorable factor for erythroid failure in MDS contributing to 27.8 – 31.4% of the degree of anemia (hemogloblin level of peripheral blood; P < 0.0000001) independently of all other pathologic changes of erythropoiesis, such as dysplasia, impaired maturation, and increased apoptosis of erythoid precursors. Its significance was independent of occurrence of marrow fibrosis and karyotype aberrations that were associated with anemia in MDS. In MDS with deletion of the long arm of chromsome 5 (5q31-33), impaired formation of Ery-Is appeared to relate to the insufficiency (reduced mRNA expression) of a gene of the common deleted region, SPARC (P < 0.00001), rather than to a haploinsufficiency of the gene encoding for the ribosomal protein #14 (P > 0.05) which influenced the rate of apoptosis of erythropoietic cells (P < 0.00001), and increased formation of Ery-Is following an upregulation of SPARC gene expression seemed to play a central role in erythroid response and prolonged AML-free survival time during lenalidomide therapy (P < 0.00001). In multivariate analysis, impaired formation or loss of Ery-Is detected on the day of diagnosis of MDS predicted the risk of the evolution of severe progressive transfusion-dependent anemia during the further course of MDS (P = 0.003) as well as the risk of shortened (AML-free) survival time of patients (P < 0.000005) independently of other known prognostic factors, such as the type of MDS (WHO classification), marrow fibrosis, cellularity, atypical localization of blasts, karyotype aberration, and prognostic groups (IPSS-R). Conclusion: Impaired formation, disruption or loss of the niches of erythropoiesis, the Ery-Is, appear to play a central role in erythroid failure in MDS independently of other dysplastic features of erythropoiesis, a novel observation, and this alteration seems to be relevant for the prognosis of disease. Therefore, the niche of erythropoiesis, the Ery-I, is worth considering and evaluating in more detail in patients with MDS.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH