MLL-REARRANGED B LYMPHOBLASTIC LEUKEMIAS SELECTIVELY EXPRESS THE IMMUNOREGULATORY CARBOHYDRATE-BINDING PROTEIN GALECTIN-1

PRZEMYSLAW JUSZCZYNSKI; SCOTT J. RODIG; JING OUYANG; EVAN O´DONNELL; KUNIHIKO TAKEYAMA; WOJCIECH MLYNARSKI; KATARZYNA MYCKO; TOMASZ SZCZEPANSKI; ANNA GAWORCZYK; ANDREI KRIVTSOV; JOERG FABER; AMIT U. SINHA; GABRIEL A. RABINOVICH; SCOTT A. ARMSTRONG; JEFFERY L. KUTOK; MARGARET A. SHIPP

CLINICAL CANCER RESEARCH

AMERICAN ASSOCIATION OF CANCER RESEARCH

Lugar: PHILADELPHIA; Año: 2010

1078-0432

Purpose: Patients with mixed lineage leukemia (MLL)–rearranged B-lymphoblastic leukemias (B-ALL) have an unfavorable prognosis and require intensified treatment. Multiple MLL fusion partners have been identified, complicating the diagnostic evaluation of MLL rearrangements. We analyzed molecular markers of MLL rearrangement for use in rapid diagnostic assays and found the immunomodulatory protein, Galectin-1 (Gal-1), to be selectively expressed in MLL-rearranged B-ALL. Experimental Design: Transcriptional profiling of ALL subtypes revealed selective overexpression of Gal-1 in MLL-rearranged ALLs. For this reason, we analyzed Gal-1 protein expression in MLL-germline and MLL-rearranged adult and infant pediatric B-ALLs and cell lines by immunoblotting, immunohistochemistry, and intracellular flow cytometry of viable tumor cell suspensions. Because deregulated gene expression in MLL-rearranged leukemias may be related to the altered histone methyltransferase activity of MLL fusion protein complex, we also analyzed histone H3 lysine 79 (H3K79) dimethylation in the LGALS1 promoter region using chromatin immunoprecipitation. Results: Gal-1 transcripts were significantlymore abundant inMLL-rearranged B-ALLs. All 32 primaryMLLrearranged B-ALLs exhibited abundant Gal-1 immunostaining, regardless of the translocation partner, whereas only 2 of 81 germline-MLL B-ALLs expressed Gal-1. In addition, Gal-1 was selectively detected in newly diagnosed MLL-rearranged B-ALLs by intracellular flow cytometry. The LGALS1 promoter H3K79 was significantly hypermethylated in MLL-rearranged B-ALLs compared with MLL-germline B-ALLs and normal pre-B cells. Conclusion: In B-ALL, Gal-1 is a highly sensitive and specific biomarker of MLL rearrangement that is Q2 likely induced by a MLL-dependent epigenetic modification. Clin Cancer Res; 16(7); OF1–9. ©2010 AACR.