Methionine-induced hyperhomocysteinemia reverts fibrinolytic pathway activation in a murine model of acute promyelocytic leukemia

Author(s):Show less -

Jacomo, Rafael H. ^{[1, 2]} ; Santana-Lemos, Barbara A. ^[1] ; Lima, Ana Silvia G. ^[1] ; Assis, Patricia A. ^[1] ; Lange, Ana Paula A. ^[1] ; Figueiredo-Pontes, Lorena L. ^[1] ; Oliveira, Luciana O. ^[1] ; Bassi, Sarah C. ^[1] ; Benicio, Mariana T. L. ^[1] ; Baggio, Marcia S. ^[1] ; Garcia, Aglair B. ^[1] ; Falcao, Roberto P. ^[1] ; Rego, Eduardo M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Div Hematol Oncol, Dept Internal Med, Med Sch Ribeirao Preto, Natl Inst Sci & Technol St, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Lab Sabin, Brasilia, DF - Brazil

• Document type: Journal article
• Source: Blood; v. 120, n. 1, p. 207-213, JUL 5 2012.
• Web of Science Citations: 11

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 mu mol/mL and < 6.0 mu mol/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. (Blood. 2012;120(1):207-213) (AU)

• FAPESP's process: 98/14247-6 - Center for Research on Cell-Based Therapy
• Grantee: Marco Antonio Zago
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC