[1280] Selective Expression of the Immunoregulatory Lectin, Galectin-1, Identifies Precursor B Cell Acute Lymphoblastic Leukemias (ALL) with MLL Rearrangements

SJ Rodig, P Juszczynski, K Takeyama, J Ouyang, J Faber, S Armstrong, MA Shipp, JL Kutok. Brrigham & Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Children's Hospital, Boston, MA

Background: Translocations of the mixed lineage leukemia (MLL) gene on chromosome 11q23 are found in over 70% of infant leukemia and associated with a poor prognosis. MLL translocations generate a new chimeric gene, in which N-terminal portion of MLL is fused to C-terminal sequence from multiple different partners. Given the variety of MLL fusion partners, molecular techniques such as FISH or Southern blotting are not able to detect all genetic abnormalities involving MLL. In addition, these time-consuming techniques are not always available at initial diagnosis.
Design: To identify molecular markers of MLL translocation that might be used in rapid diagnostic assays, we compared the transcriptional profiles of primary ALLs with and without MLL translocations. Galectin-1 (Gal1) transcripts were significantly more abundant in MLL-rearranged ALLs (MLL-ALL) from two extensive and independent datasets.
Results: Consistent with the differences in transcript abundance, Gal1 protein was significantly more abundant in MLL+ ALL cell lines than in MLL- ALL lines by western blotting. To assess the diagnostic utility of Gal1 expression in ALL subtypes, we performed Gal1 immunostaining of a large series of primary ALLs with known MLL status. All MLL-rearranged pre-B ALLs had abundant Gal1 expression (10/10 cases, 100%); in marked contrast, only 1 of 38 pre-B ALLs without an MLL translocation expressed Gal1 (3%), p<0.001. We also evaluated Gal1 expression in ALL subtypes by flow immunophenotyping and found its expression to be specific to MLL+ cells. The deregulated gene expression in MLL+ leukemias may be related to the altered histone methyltransferase activity. Thus, we analyzed histone 3 lysine 79 (H3K79) dimethylation in the Gal1 promoter region and found that it was 5 fold higher in MLL+ pre-B ALL cells than in control cells, suggesting that this epigenetic modification may be a means for Gal1 overexpression in MLL.
Conclusions: We conclude that: 1) Gal1 is a novel, highly specific marker of ALLs harboring an MLL translocation. 2) Detection of Gal1 by immunohistochemical staining or flow immunophenotyping is amenable to routine diagnostic pathology, and 3) Gal1 overexpression is likely driven by the altered histone methyltransferase activity of the MLL fusion protein complex.
Category: Hematopathology

Tuesday, March 10, 2009 1:00 PM

Platform Session: Section D, Tuesday Afternoon