title: Methionine-induced hyperhomocysteinemia reverts fibrinolytic pathway activation in a murine model of acute promyelocytic leukemia.
abstract: Increased fibrinolysis is an important component of acute promyelocytic leukemia (APL) bleeding diathesis. APL blasts overexpress annexin II (ANXII), a receptor for tissue plasminogen activator (tPA), and plasminogen, thereby increasing plasmin generation. Previous studies suggested that ANXII plays a pivotal role in APL coagulopathy. ANXII binding to tPA can be inhibited by homocysteine and hyperhomocysteinemia can be induced by L-methionine supplementation. In the present study, we used an APL mouse model to study ANXII function and the effects of hyperhomocysteinemia in vivo. Leukemic cells expressed higher ANXII and tPA plasma levels (11.95 ng/mL in leukemic vs 10.74 ng/mL in wild-type; P = .004). In leukemic mice, administration of L-methionine significantly increased homocysteine levels (49.0 μmol/mL and < 6.0 μmol/mL in the treated and nontreated groups, respectively) and reduced tPA levels to baseline concentrations. The latter were also decreased after infusion of the LCKLSL peptide, a competitor for the ANXII tPA-binding site (11.07 ng/mL; P = .001). We also expressed and purified the p36 component of ANXII in Pichia methanolica. The infusion of p36 in wild-type mice increased tPA and thrombin-antithrombin levels, and the latter was reversed by L-methionine administration. The results of the present study demonstrate the relevance of ANXII in vivo and suggest that methionine-induced hyperhomocysteinemia may reverse hyperfibrinolysis in APL.
authors.affiliation: National Institute of Science and Technology in Stem Cell and Cell Therapy, Division of Oncology/Hematology, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Rafael H
authors.initials: RH
authors.lastname: Jácomo
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Santana-Lemos
authors.forename: Ana Silvia G
authors.initials: AS
authors.lastname: Lima
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Assis
authors.forename: Ana Paula A
authors.initials: AP
authors.lastname: Lange
authors.forename: Lorena L
authors.initials: LL
authors.lastname: Figueiredo-Pontes
authors.forename: Luciana O
authors.initials: LO
authors.lastname: Oliveira
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Bassi
authors.forename: Mariana T L
authors.initials: MT
authors.lastname: Benício
authors.forename: Márcia S
authors.initials: MS
authors.lastname: Baggio
authors.forename: Aglair B
authors.initials: AB
authors.lastname: Garcia
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Falcão
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Rego
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism* / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology*; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000139:chemically induced*; D015473:Leukemia, Promyelocytic, Acute / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000097:blood
chemical_list: D017306:Annexin A2; D011994:Recombinant Proteins; D006710:Homocysteine; D008715:Methionine; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin