A NOVEL TRANSCRIPT ENCODING AN N-TERMINALLY TRUNCATED AML1 PEBP2-ALPHA-B PROTEIN INTERFERES WITH TRANSACTIVATION AND BLOCKS GRANULOCYTIC DIFFERENTIATION OF 32DC13 MYELOID CELLS/

The gene AML1/PEBP2 alpha B encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal live r hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms ha ve been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities, We have ide ntified a new isoform of the AML1 transcript, termed AML1 Delta N, in which exon I is directly connected to exon 4 by alternative splicing. The AML1 Delta N transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protec tion and reverse transcriptase PCR analyses. The protein product, of A ML1 Delta N lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the be ta subunit. However, AML1 Delta N was found to interfere with the tran sactivation activity of PEBP2, and the molecular region responsible fo r this activity was identified. Stable expression of AML1 Delta N in 3 2Dc13 myeloid cells blocked granulocytic differentiation in response t o granulocyte colony-stimulating factor. These results suggest that AM L1 Delta N acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AM L1.