ORIGINAL PAPER The relationship of the active and latent forms of TGF-b1 with marrow fibrosis in essential thrombocythemia and primary myelofibrosis Cesar Cilento Ponce • Maria de Lourdes F. Chauffaille • Silvia Saiuli M. Ihara • Maria Regina R. Silva Received: 10 December 2011 / Accepted: 15 December 2011 / Published online: 27 December 2011 Ó Springer Science+Business Media, LLC 2011 Abstract The aim of this study was to perform an immunohistochemical analysis from 100 megakaryocytes per sample, analyzing positivity and intensity levels of anti-LAP human TGF-b1 (or Latent TGF-b1) and anti- TGF-b1 (or Active TGF-b1) antibodies from 18 essential thrombocythemia (ET) and 38 primary myelofibrosis (PMF) patients (being 19 pre-fibrotic and 19 fibrotic). Six bone marrow donor biopsies were used as controls. Fibrosis in bone marrow biopsies (BMB) was evaluated according to the European Consensus. The average fibrosis grade differed between each group (P = 0.001 or P = 0.003). Latent TGF-b1 values differed significantly between pre- fibrotic (P = 0.018) and fibrotic (P = 0.031) groups when compared with the control group. The high immunoex- pression level of Latent TGF-b1 in the megakaryocytes from patients with myelofibrosis, which was not observed in patients with essential thrombocythemia, may be asso- ciated with the development of bone marrow fibrosis. Keywords Latent TGF-b1 Á Active TGF-b1 Á Megakaryocytes Á Primary myelofibrosis Á Essential thrombocythemia Á Immunohistochemistry Á Fibrosis Introduction Chronic myeloproliferative neoplasms (MPNs) were grouped for the first time in 1951 by William Dameshek, who noticed the phenotypic similarities and characteristics common to chronic myeloid leukemia (CML), polycythe- mia vera (PV), essential thrombocythemia (ET), and pri- mary myelofibrosis (PMF) [1]. These diseases are rare and altogether present an incidence of 1 case/100,000 individ- uals/year in the North-American population [2]. MPNs are clonal proliferations of hematopoietic stem cells that are characterized by the multiplication of one or more lineages, developing with medullary hypercellularity and effective maturation [3]. ET and PMF in both phases (pre-fibrotic and fibrotic stages) are most easily categorized histologically by the characteristics of associated megakaryocytes [4]. According to the World Health Organization (WHO), the main histological criteria for the differential diagnosis between these two diseases is the development of fibrosis, which is minimal or absent in ET and present in varying degrees in PMF, thus predisposing the patient to a poor prognosis [5, 6]. A growing body of evidence suggests that increased deposition of bone marrow stromal fibers is mediated by transforming growth factor-b (TGF-b) and other factors released by megakaryocytes, but it is likely that other cells, cytokines, and growth factors are also involved [7]. TGF-b is a multifunctional cytokine consisting of a 25-kDa homodimeric protein, composed of two subunits linked by disulfide bonds [8]. There are three isoforms found in mammals, TGF-b1, TGF-b2, and TGF-b3, with TGF-b1 being the most abundant isoform. TGF-b is syn- thesized as an inactive form (Latent TGF-b) by various cells (epithelial, endothelial, hematopoietic, neuronal, and C. C. Ponce (&) Á S. S. M. Ihara Á M. R. R. Silva Department of Pathology, Universidade Federal de Sa ˜o Paulo, Vicente de Carvalho Avenue, 65, # 72, Sa ˜o Paulo, Santos 11045-501, Brazil e-mail: cesarcponce@gmail.com M. de Lourdes F. Chauffaille Department of Hematology, Universidade Federal de Sa ˜o Paulo, Sa ˜o Paulo, Brazil 123 Med Oncol (2012) 29:2337–2344 DOI 10.1007/s12032-011-0144-1