RESUMO
Myelodysplastic syndromes (MDS) are preleukemic disorders characterized by clonal growth of mutant hematopoietic stem and progenitor cells. MDS are associated with proinflammatory signaling, dysregulated immune response, and cell death in the bone marrow (BM). Aging, autoinflammation and autoimmunity are crucial features of disease progression, concordant with promoting growth of malignant clones and accumulation of mutations. Suprabasin (SBSN), a recently proposed proto-oncogene of unknown function, physiologically expressed in stratified epithelia, is associated with poor prognosis of several human malignancies. Here, we showed that SBSN is expressed in the BM by myeloid cell subpopulations, including myeloid-derived suppressor cells, and is secreted into BM plasma and peripheral blood of MDS patients. The highest expression of SBSN was present in a patient group with poor prognosis. SBSN levels in the BM correlated positively with blast percentage and negatively with CCL2 chemokine levels and lymphocyte count. In vitro treatment of leukemic cells with interferon-gamma and demethylating agent 5-azacytidine (5-AC) induced SBSN expression. This indicated that aberrant cytokine levels in the BM and epigenetic landscape modifications in MDS patients may underlie ectopic expression of SBSN. Our findings suggest SBSN as a candidate biomarker of high-risk MDS with a possible role in disease progression and therapy resistance.
Assuntos
Antígenos de Diferenciação/metabolismo , Medula Óssea/metabolismo , Síndromes Mielodisplásicas/metabolismo , Proteínas de Neoplasias/metabolismo , Antígenos de Diferenciação/sangue , Antígenos de Diferenciação/genética , Azacitidina/farmacologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Compartimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Interferon gama/farmacologia , Leucócitos Mononucleares/metabolismo , Contagem de Linfócitos , Síndromes Mielodisplásicas/sangue , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Prognóstico , Proto-Oncogene Mas , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Lenalidomide therapy represents meaningful progress in the treatment of anemic patients with myelodysplastic syndromes with del(5q). We present our initial lenalidomide experience and the positive effect of combining erythropoietin and steroids with lenalidomide in refractory and relapsed patients. We treated by lenalidomide 55 (42 female; 13 male; median age 69) chronically transfused lower risk MDS patients with del(5q) (45) and non-del(5q) (10). Response, meaning transfusion independence (TI) lastingâ¯≥â¯eight weeks, was achieved in 38 (90%) of analyzed patients with del(5q), of whom three achieved TI only by adding erythropoietin⯱â¯prednisone. Another five patients responded well to this combination when their anemia relapsed later during the treatment. In the non-del(5q) group only one patient with RARS-T reached TI. Cytogenetic response was reached in 64% (32% complete, 32% partial response). The TP53 mutation was detected in 7 (18%) patients; four patients progressed to higher grade MDS or acute myeloid leukemia (AML). All seven RAEB-1 patients cleared bone marrow blasts during lenalidomide treatment and reached complete remission (CR); however, three later progressed to higher grade MDS or AML. Lenalidomide represents effective treatment for del(5q) group and combination with prednisone and erythropoietin may be used for non-responders or therapy failures.