The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Miguel Muñoz - One of the best experts on this subject based on the ideXlab platform.
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Human acute myeloid leukemia cells express Neurokinin-1 receptor, which is involved in the antileukemic effect of Neurokinin-1 receptor antagonists
Investigational New Drugs, 2019Co-Authors: A. Molinos-quintana, P. Trujillo-hacha, J. I. Piruat, J. A. Bejarano-garcía, E. García-guerrero, J. A. Pérez-simón, Miguel MuñozAbstract:The substance P/neurokinin-1 receptor system has been implicated in tumor cell proliferation. Neurokinin-1 receptor has been identified in different solid tumors but not frequently in hematopoietic malignant cells. We investigated the presence of the Neurokinin-1 receptor in acute myeloid leukemia cell lines (KG-1 and HL-60), demonstrating that acute myeloid leukemia cell lines overexpress the truncated Neurokinin-1 receptor isoform compared with lymphocytes from healthy donors. Using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) method, we demonstrated that substance P induced cell proliferation in both acute myeloid leukemia cell lines. We also observed that four different Neurokinin-1 receptor antagonists (L-733,060, L-732,138, CP 96–345 and aprepitant) elicited inhibition of acute myeloid leukemia cell growth lines in a concentration-dependent manner, while growth inhibition was only marginal in lymphocytes; the specific antitumor action of Neurokinin-1 receptor antagonists occurs via the Neurokinin-1 receptor, and leukemia cell death is due to apoptosis. Finally, administration of high doses of daily intraperitoneal fosaprepitant to NOD scid gamma mice previously xenografted with the HL60 cell line increased the median survival from 4 days (control group) to 7 days (treated group) ( p = 0.059). Taken together, these findings suggest that Neurokinin-1 receptor antagonists suppress leukemic cell growth and may be considered to be potential antitumor drugs for the treatment of human acute myeloid leukemia.
Animesh D Pardanani - One of the best experts on this subject based on the ideXlab platform.
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MPL515 mutations in myeloproliferative and other myeloid disorders: A study of 1182 patients
Blood, 2006Co-Authors: Animesh D Pardanani, Yana Pikman, Ruben A. Mesa, Martha Wadleigh, Michelle A. Elliott, Alexandra P. Wolanskyj, David P. Steensma, Terra Lasho, Ross L Levine, William J. HoganAbstract:Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.
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Atypical myeloproliferative disorders: diagnosis and management.
Mayo Clinic proceedings. Mayo Clinic, 2006Co-Authors: Ayalew Tefferi, Michelle A. Elliott, Animesh D PardananiAbstract:Myeloid disorders constitute a subgroup of hematological malignancies that is separate from lymphoid disorders. The World Health Organization system for classification of tumors of the hematopoietic system divides myeloid disorders into acute myeloid leukemia and chronic myeloid disorders based on the presence or absence, respectively, of acute myeloid leukemia--defining morphological and cytogenetic features including the presence of 20% or more myeloblasts in either the bone marrow or the peripheral blood. A recently proposed semimolecular classification system for chronic myeloid disorders recognizes 3 broad categories: the myelodysplastic syndrome, classic myeloproliferative disorders (MPD), and atypical MPD. Classic MPD includes polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and chronic myeloid leukemia. Both myelodysplastic syndrome and BCR/ABL-negative classic MPD were previously discussed as part of the current ongoing symposium on hematological malignancies. The current review focuses on the diagnosis and treatment of both molecularly defined and clinicopathologically assigned categories of atypical MPD: chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic neutrophilic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, idiopathic eosinophilia including hypereosinophilic syndrome, systemic mastocytosis, unclassified MPD, and eosinophilic/mast cell disorders associated with mutations of platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB), FGFR1, and KIT.
Lee-yung Shih - One of the best experts on this subject based on the ideXlab platform.
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RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia
Journal of Hematology & Oncology, 2019Co-Authors: Rabindranath Bera, Ming-chun Chiu, Ying-jung Huang, Tung-huei Lin, Ming-chung Kuo, Lee-yung ShihAbstract:BackgroundAdditional sex combs-like 1 ( ASXL1 ) mutations have been described in all forms of myeloid neoplasms including chronic myelomonocytic leukemia (CMML) and associated with inferior outcomes, yet the molecular pathogenesis of ASXL1 mutations ( ASXL1 -MT) remains poorly understood. Transformation of CMML to secondary AML (sAML) is one of the leading causes of death in CMML patients. Previously, we observed that transcription factor RUNX1 mutations ( RUNX1 -MT) coexisted with ASXL1 -MT in CMML and at myeloid blast phase of chronic myeloid leukemia. The contribution of RUNX1 mutations in the pathogenesis of myeloid transformation in ASXL1 -mutated leukemia, however, remains unclear.MethodsTo evaluate the leukemogenic role of RUNX1-MT in ASXL1 -mutated cells, we co-expressed RUNX1 -MT (R135T) and ASXL1 -MT (R693X) in different cell lines and performed immunoblot, co-immunoprecipitation, gene expression microarray, quantitative RT-PCR, cell proliferation, differentiation, and clonogenic assays for in vitro functional analyses. The in vivo effect was investigated using the C57BL/6 mouse bone marrow transplantation (BMT) model.ResultsCo-expression of two mutant genes increased myeloid stem cells in animal model, suggesting that cooperation of RUNX1 and ASXL1 mutations played a critical role in leukemia transformation. The expression of RUNX1 mutant in ASXL1 -mutated myeloid cells augmented proliferation, blocked differentiation, and increased self-renewal activity. At 9 months post-BMT, mice harboring combined RUNX1 and ASXL1 mutations developed disease characterized by marked splenomegaly, hepatomegaly, and leukocytosis with a shorter latency. Mice transduced with both ASXL1 and RUNX1 mutations enhanced inhibitor of DNA binding 1 (ID1) expression in the spleen, liver, and bone marrow cells. Bone marrow samples from CMML showed that ID1 overexpressed in coexisted mutations of RUNX1 and ASXL1 compared to normal control and either RUNX1 -MT or ASXL1 -MT samples. Moreover, the RUNX1 mutant protein was more stable than WT and increased HIF1-α and its target ID1 gene expression in ASXL1 mutant cells.ConclusionThe present study demonstrated the biological and functional evidence for the critical role of RUNX1 -MT in ASXL1 -mutated leukemia in the pathogenesis of myeloid malignancies.
Attilio Orazi - One of the best experts on this subject based on the ideXlab platform.
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Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases.
Pathobiology : journal of immunopathology molecular and cellular biology, 2007Co-Authors: Attilio OraziAbstract:In spite of the impressive advances in the area of molecular pathology, bone marrow morphology remains the diagnosis cornerstone to identify the various subtypes of myeloid neoplasms. Morphological examination of the bone marrow requires both bone marrow aspirate and bone marrow trephine biopsy. Immunohistochemistry of bone marrow biopsy with markers reactive in paraffin-embedded tissues represents a powerful diagnostic tool; its results can be easily correlated with those obtained by other techniques such as flow cytometry and genetic analysis, and above all, the clinical findings. The role of the bone marrow biopsy will be particularly stressed in this review article. Particular emphasis is being given to the correct identification of cases of myeloid neoplasms associated with myelofibrosis and for which the bone marrow biopsy represents the only available diagnostic mean. Moreover, the often low cellular yield of the bone marrow aspirate in these cases may also be insufficient to obtain adequate cytogenetic information. Such cases include two subtypes of acute myeloid leukemia which typically cause diagnostic difficulties: acute megakaryoblastic leukemia and acute panmyelosis with myelofibrosis (acute myelosclerosis). Acute myeloid leukemia with multilineage dysplasia, therapy-related myelodysplastic syndrome/therapy-related acute myeloid leukemia and de novo myelodysplastic syndromes (MDS) will also be discussed. The value of bone marrow biopsy in this group of disorders is generally well established. In MDS, in particular, bone marrow biopsy may help in confirming a suspected diagnosis by excluding reactive conditions in which dyshematopoietic changes may also be observed. It can increase the diagnostic accuracy and helps in refining the IPPS risk evaluation system. Among the alterations detected by bone marrow biopsy, a prognostically important finding is the presence of aggregates or clusters of immature myeloid precursor cells (myeloblasts and promyelocytes). These can also be identified by immunohistochemistry with CD34, an antigen expressed in progenitor and early precursor marrow cells, which can be used to demonstrate pathological accumulations of blasts in aggressive subtypes of myeloid neoplasms. Immunohistologic analysis is especially helpful in cases of MDS with fibrosis and cases with hypocellular marrows (hypoplastic MDS). In both of these variants, the presence of reticulin fibrosis or fatty changes in the bone marrow can make accurate disease characterization very difficult or impossible using bone marrow aspirates. Finally, the important group of the myelodysplastic/myeloproliferative disorders can only be accurately categorized by a careful multiparametric approach in which the bone marrow biopsy exerts a pivotal role.
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Morphologic and immunohistochemical evaluation of splenic hematopoietic proliferations in neoplastic and benign disorders
Modern Pathology, 2005Co-Authors: Dennis P O'malley, Sherrie L Perkins, Leeann Baldridge, Beth E Juliar, Attilio OraziAbstract:Spleen is a common site of extramedullary hematopoiesis. Extramedullary hematopoiesis seen in non-neoplastic conditions can occasionally be extensive and raise concerns for a myeloid neoplasm. We compared the morphologic and immunohistochemical features of splenic hematopoietic proliferations seen in neoplastic myeloid disorders (eg chronic myeloproliferative disorders, myelodysplastic/myeloproliferative disorders and acute myeloid leukemias) to extramedullary hematopoiesis seen in a variety of reactive conditions. In all, 80 spleen specimens were reviewed. The presence of each marrow-derived lineage, dysplasia and immunohistochemical results were evaluated (CD34, CD117, myeloperoxidase, CD68, p53, TdT, CD42b and hemoglobin). Neoplastic hematopoietic proliferations in chronic myeloproliferative disorders are characterized by trilineage hematopoiesis with significant dysplasia in all cell lineages. Acute myeloid leukemia showed an increase in immature forms, which were highlighted by immunohistochemistry. Reactive extramedullary hematopoiesis showed variability in histologic features. Post-bone marrow transplant and thrombotic thrombocytopenic purpura/hemolytic–uremic syndrome spleens showed extramedullary hematopoiesis with some morphologic features of immaturity, which could simulate chronic myeloproliferative disorder. However, they lacked characteristic immunohistochemical features of neoplastic myeloid disorders such as positivity for CD34 or CD117.
Kevin A Link - One of the best experts on this subject based on the ideXlab platform.
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Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells.
The Journal of clinical investigation, 2013Co-Authors: Susumu Goyama, Mark Wunderlich, Janet Schibler, Lea Cunningham, Yalan Rao, Nahoko Nishimoto, Andre Olsson, Masahiro Nakagawa, Yue Zhang, Kevin A LinkAbstract:RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.
