Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In summary, this case illustrates a previously unrecognized syndrome of reticulocytosis secondary to a defect in reticulin degradation. We are aware of two other case reports in the literature which also describe patients with an elevated reticulocyte count who's red cells appeared to lack the ability to degrade reticulin (Lofters et. al.1978, Tulliez et. al. 1982). Both of these cases however, demonstrated only mild reticulocytosis and appeared to be related to preleukemic syndromes. Our patient had no evidence of preleukemia and indeed, has been followed for over four years without evidence of other hematologic abnormalities. The mild anemia that has persisted in this patient may suggest that although no evidence of hemolysis is obvious in this patient, some minor amount of hemolysis may be occurring. Due to the relative insensitivity of other measures of early red cell death (51Cr survival, bone marrow biopsy, etc...), and the loss of the the reticulocyte count as a sensitive index of hemolysis, a minor amount of hemolysis cannot be excluded. This does not decrease the validity of the observations noted above, since this massive reticulocytosis cannot be explained by minimal hemolysis. Whether this patient's reticulocytosis represents an acquired or congenital syndrome is unsettled at present. Although his brother is unaffected, and we have on record only a mildly elevated reticulocyte count from 1981, there remains a possibility that this syndrome is congenital. We are, at present, in the process of further characterizing the specific defect in these red cells. Further assays of Lipoxygenase and protease activity, the ability to ubiquitinate proteins, specific identification of the mitochondria-like structures, and protein synthesis assays are in progress or are planned. The inability to degrade reticulin in this patient's red cells and the impact of this upon other cellular physiologic processes afford an excellent opportunity to enhance our understanding of normal red cell physiology, particularly, we suspect in this patient, of Ubiquitin-ATP-dependent proteolysis.
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PMID:Reticulocytosis: defective reticulin degradation, a case report. 248 76

Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is driven by complex genetic and epigenetic alterations from an aberrant clone of hematopoietic stem/progenitor cells (HSPCs). Ubiquitin-specific protease 7 (USP7) has been demonstrated to have an important oncogenic role in the development of several cancer types, but its role in MDS is unknown. Here, we demonstrate that USP7 expression is elevated in MDS cell lines and patient samples. The USP7-selective small-molecule inhibitors P5091 and P22077 inhibited cell proliferation and induced megakaryocytic differentiation in both cell lines and primary cells. Furthermore, pharmacological inhibition of USP7 markedly suppressed the growth of MDS cell lines in xenograft mouse models. To explore the mechanisms underlying the observed phenotypic changes, we employed RNA-seq to compare the differences in genes after USP7 inhibitor treatment and found that gelsolin (GSN) expression was increased significantly after USP7 inhibitor treatment. Furthermore, knockdown of GSN attenuated the proliferation inhibition, apoptosis induction and megakaryocyte differentiation induced by USP7 inhibitors in MDS cells. Collectively, our findings identify previously unknown roles of USP7 and suggest that the USP7/GSN axis may be a potential therapeutic target in MDS.
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PMID:USP7 inhibition inhibits proliferation and induces megakaryocytic differentiation in MDS cells by upregulating gelsolin. 3213 Jul 29