Fli-1 Expression Is Increased in Erythroblasts in MDS with Del(5q) and Correlates with Response to Lenalidomide
Daniel F Boyer, Eyal Attar, Robert P Hasserjian. Massachusetts General Hospital, Boston
Background: Myelodysplastic syndrome (MDS) with isolated del5q has distinctive clinical and morphologic features and excellent responsivness to lenalidomide therapy. Fli-1, an ETS transcription factor, is a positive regulator of megakaryopoiesis and its overexpression suppresses erythropoiesis. FLI1 mRNA is increased in the bone marrow of patients with del5q MDS, but the distribution of Fli-1 protein in del5q MDS bone marrow and any effect of lenalidomide on Fli-1 expression are unknown.
Design: 24 bone marrow biopsy specimens (11 del5q MDS [5 untreated and 6 post-lenalidomide], 8 other MDS, and 5 non-neoplastic controls) were stained for Fli-1 by immunohistochemistry and percentage of erythroblasts (EB), megakaryocytes, and total marrow cells with nuclear Fli-1 expression determined by a blinded observer. Cellularity, myeloid:erythroid ratio, megakaryocytes/10 hpf, and percentage of dysplastic megakaryocytes were evaluated.
Results: Fli-1 protein was strongly expressed in megakaryocytes and weakly expressed in myeloids in all samples. Increased expression of Fli-1 in EB was detected in bone marrow with untreated del5q MDS or del5q MDS without cytogenetic response to lenalidomide, while few Fli-1+ EB were seen in del5q MDS patients with cytogenetic response to lenalidomide (see Table). Cytogenetic response also correlated with fewer megakaryocytes/10hpf, normalization of megakaryocyte morphology, and decreased myeloid:erythroid ratio. Of the 6 patients who were biopsied after lenalidomide therapy, 1 patient failed to show hematologic response; this was the only del5q patient with a low percentage (28%) of Fli-1+ EB prior to treatment. Non-neoplastic control specimens showed low Fli-1 expression in EB (<50% positive). Fli-1+ EB were increased (>50% positive) in 2/8 MDS marrows without del5q.
Conclusions: Fli-1 protein is strongly expressed in bone marrow from del5q MDS patients. Increased Fli-1 expression is especially prominent in del5q EB compared to EB in control marrows, and reduction in Fli-1+ EB correlated with cytogenetic response to lenalidomide. The single patient in this group with no clinical response to lenalidomide had a low percentage of Fli-1+ EB. The results of this small study raise the possibility that reduction in Fli-1 expression may be a mechanism of responsiveness to lenalidomide in MDS with del5q.
|Metaphases with del5q (%)||Fli1+ EB (%)||Mega/10hpf||Mega dysplasia (%)|