Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression.

Abstract:

:Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.

journal_name

Haematologica

journal_title

Haematologica

authors

Solimando AG,Da Vià MC,Leone P,Borrelli P,Croci GA,Tabares P,Brandl A,Di Lernia G,Bianchi FP,Tafuri S,Steinbrunn T,Balduini A,Melaccio A,De Summa S,Argentiero A,Rauert-Wunderlich H,Frassanito MA,Ditonno P,Henke E,Kl

doi

10.3324/haematol.2019.239913

subject

Has Abstract

pub_date

2020-04-30 00:00:00

eissn

0390-6078

issn

1592-8721

pii

haematol.2019.239913

pub_type

杂志文章
  • Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia.

    abstract::The introduction of agents inhibiting the BCR-associated kinases such as ibrutinib has dramatically changed treatments algorithms of chronic lymphocytic leukaemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as single agent, in a real-life context, on 180 patie...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2020.251488

    authors: Del Poeta G,Biagi A,Laurenti L,Chiarenza A,Pozzo F,Innocenti I,Postorino M,Rossi FM,Del Principe MI,Bomben R,de Fabritiis P,Bruno A,Cantonetti M,Di Raimondo F,Zucchetto A,Gattei V

    更新日期:2020-07-30 00:00:00

  • Return to normal values of lipid pattern after effective chemotherapy in acute lymphoblastic leukemia.

    abstract::In the present work we investigated HDL-C and its subfractions HDL2 and HDL3 as well as total cholesterol (TC), triglycerides (TG), LDL-C, VLDL-C, apolipoproteins A1 (ApoA1) and B (ApoB) and lipoprotein (a) (Lp(a) in 25 patients with newly diagnosed acute lymphocytic leukemia (ALL) before and after induction treatment...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Scribano D,Baroni S,Pagano L,Zuppi C,Leone G,Giardina B

    更新日期:1996-07-01 00:00:00

  • MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response.

    abstract:BACKGROUND:MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma. DESIGN AND METHODS:MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human micr...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2011.048132

    authors: Wang W,Corrigan-Cummins M,Hudson J,Maric I,Simakova O,Neelapu SS,Kwak LW,Janik JE,Gause B,Jaffe ES,Calvo KR

    更新日期:2012-04-01 00:00:00

  • Higher erythropoietin secretion in response to cobaltous chloride in post-hypoxic than in hypertransfused polycythemic mice.

    abstract:BACKGROUND:We have shown previously that both erythrocyte production rate (EPR) and plasma erythropoietin (EPO) levels in response to hypoxia or to compounds able to stimulate EPO secretion are very much higher in post-hypoxic (PH) than in hypertransfused (HT) polycythemic mice with similar levels of hematocrit. Since ...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Alippi RM,Boyer P,Leal T,Barcelò AC,Martinez MP,Bozzini CE

    更新日期:1992-11-01 00:00:00

  • Thrombotic and bleeding complications in four subpopulations of patients with essential thrombocythemia defined by c-Mpl protein expression and PRV-1 mRNA levels.

    abstract::C-Mpl and PRV-1 expression was measured in a cohort of 48 patients with essential thrombocythemia (ET). A retrospective analysis was conducted to asses whether the presence of one or both markers correlates with a higher risk of developing thromboembolic complications. In this cohort, PRV-1 overexpression was associat...

    journal_title:Haematologica

    pub_type: 信件

    doi:

    authors: Goerttler PL,März E,Johansson PL,Andreasson B,Kutti J,Moliterno AR,Marchioli R,Spivak JL,Pahl HL,MPD Research Consortium.

    更新日期:2005-06-01 00:00:00

  • Comparative evaluation of differential leukocyte counts by Coulter VCS cytometer and direct microscopic observation.

    abstract::Comparative analyses of the leukocyte differential counting were performed using a Coulter VCS Hematology Flow Cytometer and direct microscopic observation on 547 unselected individuals analyzed at the outpatient clinic of the Institute of Hematology "L. e A. Seràgnoli" of Bologna. The Coulter VCS is able to provide l...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Zaccaria A,Celso B,Raspadori D,Motta MR,Testoni N,Rizzi S

    更新日期:1990-09-01 00:00:00

  • A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study.

    abstract::In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase togethe...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2016.144535

    authors: Chiaretti S,Vitale A,Vignetti M,Piciocchi A,Fazi P,Elia L,Falini B,Ronco F,Ferrara F,De Fabritiis P,Luppi M,La Nasa G,Tedeschi A,Califano C,Fanin R,Dore F,Mandelli F,Meloni G,Foà R

    更新日期:2016-12-01 00:00:00

  • Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes.

    abstract::Disease bulk is an important prognostic factor in early stage Hodgkin lymphoma, but its definition is unclear in the computed tomography era. This retrospective analysis investigated the prognostic significance of bulky disease measured in transverse and coronal planes on computed tomography imaging. Early stage Hodgk...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2016.141846

    authors: Kumar A,Burger IA,Zhang Z,Drill EN,Migliacci JC,Ng A,LaCasce A,Wall D,Witzig TE,Ristow K,Yahalom J,Moskowitz CH,Zelenetz AD

    更新日期:2016-10-01 00:00:00

  • Recovery of polyclonal immunoglobulins one year after autologous stem cell transplantation as a long-term predictor marker of progression and survival in multiple myeloma.

    abstract::Immunoparesis or suppression of polyclonal immunoglobulins is a very common condition in newly diagnosed myeloma patients. However, the recovery of polyclonal immunoglobulins in the setting of immune reconstitution after autologous stem cell transplantation and its effect on outcome has not yet been explored. We condu...

    journal_title:Haematologica

    pub_type: 杂志文章,多中心研究

    doi:10.3324/haematol.2016.158345

    authors: González-Calle V,Cerdá S,Labrador J,Sobejano E,González-Mena B,Aguilera C,Ocio EM,Vidriales MB,Puig N,Gutiérrez NC,García-Sanz R,Alonso JM,López R,Aguilar C,de Coca AG,Hernández R,Hernández JM,Escalante F,Mateos MV

    更新日期:2017-05-01 00:00:00

  • Red cell aplasia and autoimmune hemolytic anemia following immunosuppression with alemtuzumab, mycophenolate, and daclizumab in pancreas transplant recipients.

    abstract:BACKGROUND AND OBJECTIVES:Acquired red cell aplasia (RCA) is a rare disorder and can be either idiopathic or associated with certain diseases, pregnancy, or drugs. In exceptionally rare cases, it has been reported to co-exist with other autoimmune cytopenias. We report a high incidence of RCA and autoimmune hemolytic a...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.10733

    authors: Elimelakh M,Dayton V,Park KS,Gruessner AC,Sutherland D,Howe RB,Reding MT,Eastlund T,van Burik JA,Singleton TP,Gruessner RW,Key NS

    更新日期:2007-08-01 00:00:00

  • Efficient gene transfer into primitive hematopoietic progenitors using a bone marrow microenvironment cell line engineered to produce retroviral vectors.

    abstract:BACKGROUND AND OBJECTIVES:Effective gene transfer into human hematopoietic stem/progenitor cells is a compromise between achieving high transduction efficiency and maintaining the desired biological characteristics of the target cell. The aim of our work was to exploit the stromal microenvironment to increase gene tran...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Dando JS,Ficara F,Deola S,Roncarolo MG,Bordignon C,Aiuti A

    更新日期:2004-04-01 00:00:00

  • B-cell involvement in chronic graft-versus-host disease.

    abstract::Chronic graft-versus-host disease is a serious complication in long-term survivors of allogeneic hematopoietic stem cell transplantation, with several organ systems affected. Chronic graft-versus-host disease is an important cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. This a...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.13311

    authors: Kapur R,Ebeling S,Hagenbeek A

    更新日期:2008-11-01 00:00:00

  • Resistance to activated protein C as a risk factor of stroke in a thalassemic patient.

    abstract::It is well known that thalassemic patients exhibit an increased frequency of thrombotic events. Most individuals with resistance to activated protein C (APCR) are the result of a point mutation replacing Arg 506 with Gln in the factor V aminoacidic sequence (factor V Leiden). Recently APCR has been shown to account fo...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Giordano P,Sabato V,Schettini F,De Mattia D,Iolascon A

    更新日期:1997-11-01 00:00:00

  • Megakaryocyte volume modulates bone marrow niche properties and cell migration dynamics.

    abstract::All hematopoietic cells that develop in the bone marrow must cross the endothelial barrier to enter the blood circulation. Blood platelets, however, are released by bigger protrusions of huge progenitor cells, named megakaryocytes, and enter the blood stream as so-called proplatelets before fragmenting into mature pla...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2018.202010

    authors: Gorelashvili MG,Angay O,Hemmen K,Klaus V,Stegner D,Heinze KG

    更新日期:2020-04-01 00:00:00

  • Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C.

    abstract::Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis vir...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.12554

    authors: Di Marco V,Capra M,Gagliardotto F,Borsellino Z,Cabibi D,Barbaria F,Ferraro D,Cuccia L,Ruffo GB,Bronte F,Di Stefano R,Almasio PL,Craxì A

    更新日期:2008-08-01 00:00:00

  • Loss of HLA-DR expression and immunoblastic morphology predict adverse outcome in diffuse large B-cell lymphoma - analyses of cases from two prospective randomized clinical trials.

    abstract:BACKGROUND:Research on prognostically relevant immunohistochemical markers in diffuse large B-cell lymphomas has mostly been performed on retrospectively collected clinical data. This is also true for immunohistochemical classifiers that are thought to reflect the cell-of-origin subclassification of gene expression stu...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2009.008862

    authors: Bernd HW,Ziepert M,Thorns C,Klapper W,Wacker HH,Hummel M,Stein H,Hansmann ML,Ott G,Rosenwald A,Müller-Hermelink HK,Barth TF,Möller P,Cogliatti SB,Pfreundschuh M,Schmitz N,Trümper L,Höller S,Löffler M,Feller AC,Ger

    更新日期:2009-11-01 00:00:00

  • International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia.

    abstract::Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leuke...

    journal_title:Haematologica

    pub_type: 杂志文章,多中心研究

    doi:10.3324/haematol.2016.144311

    authors: Gökbuget N,Dombret H,Ribera JM,Fielding AK,Advani A,Bassan R,Chia V,Doubek M,Giebel S,Hoelzer D,Ifrah N,Katz A,Kelsh M,Martinelli G,Morgades M,O'Brien S,Rowe JM,Stieglmaier J,Wadleigh M,Kantarjian H

    更新日期:2016-12-01 00:00:00

  • Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice.

    abstract::Acquired aplastic anemia is an autoimmune-mediated bone marrow failure syndrome. The mechanism by which such an autoimmune reaction is initiated is unknown. Whether and how the genetic lesions detected in patients cause autoimmune bone marrow failure have not yet been determined. We found that mice with spontaneous de...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2016.151514

    authors: Xin J,Breslin P,Wei W,Li J,Gutierrez R,Cannova J,Ni A,Ng G,Schmidt R,Chen H,Parini V,Kuo PC,Kini AR,Stiff P,Zhu J,Zhang J

    更新日期:2017-02-01 00:00:00

  • IFN-beta induced biochemical and immunological modifications in hairy cell leukemia patients.

    abstract:BACKGROUND:Although IFN-beta is 30-40% homologous with IFN-alpha, its intrinsic biological properties are not identical. Compared with IFN-alpha, IFN-beta exerts greater in vitro antiproliferative activity on many cell lines, stimulates peripheral blood stem cells of hairy-cell leukemia (HCL) patients to differentiate ...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Liberati AM,Schippa M,Portuesi MG,Grazia Proietti M,De Angelis V,Ferrajoli A,Cinieri S,Di Clemente F,Palmisano L,Berruto P

    更新日期:1991-09-01 00:00:00

  • Increased plasma thrombopoietin levels in patients with myelodysplastic syndrome: a reliable marker for a benign subset of bone marrow failure.

    abstract::Although myelodysplastic syndromes are heterogeneous disorders comprising a benign subset of bone marrow failure similar to aplastic anemia, no laboratory test has been established to distinguish it from bone marrow failures that can evolve into acute myeloid leukemia. Plasma thrombopoietin levels were measured in 120...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2012.066217

    authors: Seiki Y,Sasaki Y,Hosokawa K,Saito C,Sugimori N,Yamazaki H,Takami A,Nakao S

    更新日期:2013-06-01 00:00:00

  • Downregulation of TREM-like transcript-1 and collagen receptor α2 subunit, two novel RUNX1-targets, contributes to platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia.

    abstract::Germline RUNX1 mutations lead to thrombocytopenia and platelet dysfunction in familial platelet disorder with predisposition to acute myelogenous leukemia (AML). Multiple aspects of platelet function are impaired in these patients, associated with altered expression of genes regulated by RUNX1 We aimed to identify RUN...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2018.188904

    authors: Glembotsky AC,Sliwa D,Bluteau D,Balayn N,Marin Oyarzún CP,Raimbault A,Bordas M,Droin N,Pirozhkova I,Washington V,Goette NP,Marta RF,Favier R,Raslova H,Heller PG

    更新日期:2019-06-01 00:00:00

  • Fibrin(ogen) in human disease: both friend and foe.

    abstract::Fibrinogen is an abundant protein synthesized in the liver, present in human blood plasma at concentrations ranging from 1.5-4 g/L in healthy individuals with a normal half-life of 3-5 days. With fibrin, produced by thrombin-mediated cleavage, fibrinogen plays important roles in many physiological processes. Indeed, t...

    journal_title:Haematologica

    pub_type: 杂志文章,评审

    doi:10.3324/haematol.2019.236901

    authors: Vilar R,Fish RJ,Casini A,Neerman-Arbez M

    更新日期:2020-01-31 00:00:00

  • Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

    abstract:BACKGROUND:Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a b...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2011.054254

    authors: Swift BE,Williams BA,Kosaka Y,Wang XH,Medin JA,Viswanathan S,Martinez-Lopez J,Keating A

    更新日期:2012-07-01 00:00:00

  • Autologous blood stem cell transplantation as intensive consolidation therapy in hematological malignancies.

    abstract::Ten consecutive patients (pts), suffering from hematological malignancies (5 NHL, 3 ANLL and 2 HD), received high doses of radio-chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation. Seven of them were in 1st CR, two in 3rd CR and one in refractory status. The recruitment of PBSC was performed...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:

    authors: Fioritoni G,Iacone A,D'Antonio D,Dragani A,Quaglietta AM,Accorsi P,Angelini A,Spadano A,Natale D,Berardi A

    更新日期:1990-01-01 00:00:00

  • Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse.

    abstract::Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients trea...

    journal_title:Haematologica

    pub_type: 临床试验,杂志文章

    doi:10.3324/haematol.2014.104133

    authors: Hubmann M,Köhnke T,Hoster E,Schneider S,Dufour A,Zellmeier E,Fiegl M,Braess J,Bohlander SK,Subklewe M,Sauerland MC,Berdel WE,Büchner T,Wörmann B,Hiddemann W,Spiekermann K

    更新日期:2014-08-01 00:00:00

  • Chronic myeloid leukemia: reminiscences and dreams.

    abstract::With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pa...

    journal_title:Haematologica

    pub_type: 传,历史文章,杂志文章,评审

    doi:10.3324/haematol.2015.139337

    authors: Mughal TI,Radich JP,Deininger MW,Apperley JF,Hughes TP,Harrison CJ,Gambacorti-Passerini C,Saglio G,Cortes J,Daley GQ

    更新日期:2016-05-01 00:00:00

  • Optimizing peripheral blood progenitor cell autologous transplantation in multiple myeloma.

    abstract::As in other malignancies, peripheral blood progenitor cells (PBPC) have almost completely replaced bone marrow as the source of stem cells for autologous transplantation in multiple myeloma. PBPC collection could be optimized either by reducing contamination by the malignant clone or by increasing hematopoietic qualit...

    journal_title:Haematologica

    pub_type: 临床试验,杂志文章,随机对照试验,评审

    doi:

    authors: Harousseau JL

    更新日期:1999-06-01 00:00:00

  • Flavopiridol treatment of patients aged 70 or older with refractory or relapsed chronic lymphocytic leukemia is a feasible and active therapeutic approach.

    abstract::Older chronic lymphocytic leukemia patients have poor outcomes with standard treatments and are underrepresented in clinical trials. We retrospectively reviewed outcomes of refractory chronic lymphocytic leukemia patients in two age categories (≥70 and <70 years) treated with single-agent flavopiridol, a drug active i...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2011.047324

    authors: Stephens DM,Ruppert AS,Blum K,Jones J,Flynn JM,Johnson AJ,Ji J,Phelps MA,Grever MR,Byrd JC

    更新日期:2012-03-01 00:00:00

  • Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts.

    abstract::The control of mRNA stability plays a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation and tumorigenesis. HNRNPA0, which encodes an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements of mRNAs, is located within the commonly...

    journal_title:Haematologica

    pub_type: 杂志文章

    doi:10.3324/haematol.2013.098657

    authors: Young DJ,Stoddart A,Nakitandwe J,Chen SC,Qian Z,Downing JR,Le Beau MM

    更新日期:2014-06-01 00:00:00

  • Peering through zebrafish to understand inherited bone marrow failure syndromes.

    abstract::Inherited bone marrow failure syndromes are experiments of nature characterized by impaired hematopoiesis with cancer and leukemia predisposition. The mutations associated with inherited bone marrow failure syndromes affect fundamental cellular pathways, such as DNA repair, telomere maintenance, or proteostasis. How t...

    journal_title:Haematologica

    pub_type: 杂志文章,评审

    doi:10.3324/haematol.2018.196105

    authors: Oyarbide U,Topczewski J,Corey SJ

    更新日期:2019-01-01 00:00:00