No abstract

The overexpression of PRV-1 seems to be a useful tool for discriminating ET and PV from ST and SE, thus offering an innovative diagnostic approach on the basis of the detection of positive diagnostic criteria instead of exclusion criteria.

The mechanisms underlying acute promyelocytic leukemia (APL) coagulopathy and its reversal by administration of all-trans retinoic acid (ATRA) have been investigated. Bone marrow promyelocytic blasts from nine patients with APL were cultured with or without ATRA 1 mumol/L. Cultured blasts (days 0, 3, 6, and 9) were washed, resuspended in phosphate buffer, lysed by freezing and thawing, and then assayed for procoagulant activity (PCA), elastase activity, tissue factor (TF) antigen, tissue-type plasminogen activator (t-PA) antigen and urokinase- type plasminogen activator (u-PA) antigen. PCA was determined by a recalcification assay. Elastase was measured by an amidolytic assay (S- 2484). TF, t-PA, and u-PA antigens were measured by an enzyme-linked immunosorbent assay (ELISA). Malignant promyelocytes isolated from the patients had increased levels of PCA and TF as compared with the control polymorphonucleates, and low levels of elastase, t-PA, and u- PA; the patient blast PCA level was significantly related to the degree of hypofibrinogenemia. In this system, blast PCA depended on the tissue factor and was significantly correlated to the TF antigen values. In the cultures without ATRA, PCA, TF, and u-PA progressively increased, whereas elastase and t-PA levels remained essentially unchanged. In the presence of ATRA, all parameters (except u-PA) decreased during the culture time. Thus, a major role of the promyelocytic blast cell PCA in the pathogenesis of M3-related coagulopathy is suggested; the ATRA effect on coagulopathy seems mainly mediated by a downregulation of the PCA.

Granulocytic sarcoma (chloroma) is a rare solid, extramedullary tumour composed of immature granulocytes, occurring during granulocytic leukemia. Leukemic involvement of the temporal bone is not uncommon and may present in a variety of ways. Symptomatic facial nerve paralysis is one of these. The authors report a case of facial nerve paralysis as the presenting symptom of leukemic relapse in a 16-year-old white male, affected by acute myelogenous leukemia FAB M2, karyotype 46xy, T8;21.

In myelodysplastic syndrome (MDS), the expression of the cyclin-dependent kinase inhibitor p15 ink4B (p15) is frequently decreased because of the aberrant methylation of the gene promoter; p15 is normally up-regulated during megakaryocytic differentiation. It was hypothesized that p15 methylation and deregulation of gene expression contribute to defective megakaryocytopoiesis in patients with MDS. Here it is shown that the increasing autocrine production of TGF-␤1 stimulates megakaryocytic differentiation in normal CD34 ؉ cells and that p15 mediates, at least in part, this effect. This TGF-␤1-dependent pathway is altered in MDS CD34 ؉ progenitors because of p15 methylation. The demethylating agent 2-deoxyAZAcytidin can restore the normal demethylated state of the p15 gene and increase its expression. Nevertheless, MDS CD34 ؉ cells only poorly differentiate to the megakaryocytic lineage. These findings suggest that p15 methylation occurs in a neoplastic clone with a profound defect of cell proliferation, survival, and differentiation that cannot be overcome by using a demethylating drug. IntroductionWe have recently shown that expression of the cyclin-dependent kinase inhibitor (CDKI) p15 ink4B (p15) is up-regulated during in vitro granulocytic and megakaryocytic differentiation of normal CD34 ϩ hematopoietic progenitors. 1,2 An aberrant methylation of CpG islands in the p15 promoter region commonly occurs in myelodysplastic syndromes (MDS), such as refractory anemia with excess of blasts (RAEB) or RAEB in transformation (RAEB-t), and is associated with the loss of p15 expression. 3,4 An important function of p15 is to mediate extracellular antimitotic signals, and p15 has been identified as the effector of the G1-arrest induced by transforming growth factor ␤1 (TGF-␤1) in a keratinocyte cell line. 5 TGF-␤1 is a multifunctional hematopoietic regulator. 6 With respect to megakaryocytopoiesis, in vitro studies suggest that TGF-␤1 exerts an inhibitory effect on early and late stages of megakaryocytopoiesis, affecting both megakaryocytic differentiation and endomitosis. [7][8][9] Megakaryocytic dysplasia and thrombocytopenia are frequent findings in patients with RAEB and RAEB-t. We hypothesize that the loss of p15 expression contributes to the impaired megakaryocytic differentiation in these patients.The aims of the present study were to clarify the association between TGF-␤1 and p15 in normal megakaryocytic differentiation and to address the role of p15 methylation in the altered megakaryocytopoiesis of MDS. Study designPatients CD34 ϩ cells were isolated from bone marrow samples of 5 RAEB-free donors undergoing marrow harvest for allogeneic transplantation and from 11 patients affected by RAEB. Diagnosis was established according to the French-American-British classification. 10 The proportion of blast in the bone marrow ranged between 15% and 20%, and all patients had platelet counts less than 60 ϫ 10 9 /L. Cytogenetic analysis was performed in 7 of 11 patients: 6 patients had normal karyotype, and one patient s...