Molecular genetics may influence outcome for patients with myelofibrosis. To determine the impact of molecular genetics on outcome after allogeneic stem cell transplantation, we screened 169 patients with primary myelofibrosis (n = 110), post-essential thrombocythemia/polycythemia vera myelofibrosis (n = 46), and myelofibrosis in transformation (n = 13) for mutations in 16 frequently mutated genes. The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 21% and of relapse at 5 years 25%. The 5-year rates progression-free (PFS) and overall survival (OS) were and 56%, respectively. In a multivariate analysis CALR mutation was an independent factor for lower NRM (HR, .415; P = .05), improved PFS (HR, .393; P = .01), and OS (HR, .448; P = .03). ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [P = .008], and HR, 5.451 [P = .002], respectively), whereas no impact was observed for "triple negative" patients. Molecular genetics, especially CALR, IDH2, and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors after allogeneic stem cell transplantation for myelofibrosis.

Vascular risk factors contribute to the progression of dementia in Alzheimer's disease (AD) and influence platelet activation. However, the degree of platelet activation as a possible underlying mechanism of this progression has not been studied till now. Significantly higher baseline expression of both platelet activation biomarkers, activated glycoprotein IIb-IIIa complex and P-selectin, was observed in patients with AD with fast cognitive decline compared with AD patients with slow cognitive decline during a 1-year follow-up period. These results suggest that platelet activation could be a putative prognostic biomarker for the rate of cognitive decline and a potential new treatment target in AD patients.

ϩ cells isolated from human peripheral blood can differentiate into endothelial cells, contributing to neoangiogenesis. Since then, numerous experimental studies 2-5 investigated and further supported the role of CD34 ϩ stem cells in vascular regeneration and tissue healing. The mobilization of CD34 ϩ cells expressing early cardiac, muscle, and endothelial markers into peripheral blood was reported in patients with acute myocardial infarction. After tissue ischemia, progenitor cells are mobilized from their bone marrow or peripheral niches into circulation, adhere at sites of the vascular lesion, and differentiate into a variety of mature cell types according to their origin and the local environment. 6,7 Impairment in this pathophysiological process, as the result of either low numbers of circulating progenitor cells or dysfunctional progenitor cells, leads to inadequate vascular repair; on coexistence with different cardiovascular risk factors, this type of impairment leads to vascular injury and atherosclerosis. The level of circulating CD34 ϩ progenitor cells predicts the occurrence of cardiovascular events and death from cardiovascular causes and correlates with cardiovascular risk factors in patients with coronary artery disease. 8 Therefore, it is not surprising that a plethora of in vivo studies and clinical trials were raised to examine the therapeutic benefits of CD34 ϩ cell transplantation in ischemic disease. ϩ progenitor cells into bone marrow has been extensively studied, 11 domiciliation of CD34 ϩ precursor cells into peripheral tissues and differentiation into endothelial cells is poorly understood. The role of platelets in domiciliation and subsequent differentiation of progenitor cells has been recently highlighted. 12-17 Adherent platelets secrete a potent stem cell chemokine, the stromal cell-derived factor 1 (SDF-1); recruit circulating progenitor cells; and induce differentiation of the latter into endothelial cells. 13,15 To our knowledge, the mechanisms responsible for platelet-mediated recruitment and differentiation of CD34 ϩ cells have not been sufficiently elucidated.Junctional adhesion molecule A (JAM-A; also known as JAM-1 or F11 receptor) is a cell adhesion molecule expressed on a variety of cells, including platelets playing a crucial role in platelet adhesion and vascular inflammation. 18 The role of platelet-derived JAM-A in adhesion and differentiation of human CD34ϩ cells has not been described. The present study analyzes the role of JAM-A in the adhesion and differentiation of CD34 ϩ cells into endothelial progenitor cells. MethodsA detailed "Methods" section is given in the Supplemental Material (available online at http://atvb.ahajournals.org). Isolation and Culture of Platelets, Human CD34 ؉ Cells, and Human Arterial Endothelial CellsHuman platelets were isolated as previously described. 13,15 Human CD34 ϩ cells were isolated from either human cord blood or bone marrow and cultured as previously described. 14,15 Human arterial endothelial cells (haECs) were isolated and pa...

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We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia from MDS (sAML) to evaluate their impact on prognosis. 304 patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). In multivariate analysis, mutated NRAS, U2AF1, IDH2, TP53 and/or a complex karyotype were significant prognostic markers for OS besides age above 60 years, remission status, IPSS-R cytogenetic risk, HCT-CI > 2 and female donor sex. Mutated NRAS, IDH1, EZH2 and TP53 and/or a complex karyotype were