SPECIFIC IN-VIVO ASSOCIATION BETWEEN THE BHLH AND LIM PROTEINS IMPLICATED IN HUMAN T-CELL LEUKEMIA

The protein products of proto-oncogenes implicated in T cell acute lym phoblastic leukemia include two distinct families of presumptive trans cription factors, RBTN1 and RBTN2 encode highly related proteins that possess cysteine-rich LIM motifs. TAL1, TAL2 and LYL1 encode a unique subgroup of basic helix-loop-helix (bHLH) proteins that share exceptio nal homology in their bHLH sequences. We have found that RBTN1 and RBT N2 have the ability to interact with each of the leukemogenic bHLH pro teins (TAL1, TAL2 and LYL1). These interactions occur in vivo and appe ar to be mediated by sequences within the LIM and bHLH domains. The LI M-bHLH interactions are highly specific in that RBTN1 and RBTN2 will a ssociate with TAL1, TAL2 and LYL1, but not with other bHLH proteins, i ncluding E12, E47, Id1, NHLH1, AP4, MAX, MYC and MyoD1. Moreover, RBTN 1 and RBTN2 can interact with TAL1 polypeptides that exist in assemble d bHLH heterodimers (e.g. TAL1-E47), suggesting that the RBTN proteins can influence the functional properties of TAL1. Finally, we have ide ntified a subset of leukemia patients that harbor tumor-specific rearr angements of both their RBTN2 and TAL1 genes. Thus, the activated alle les of these genes may promote leukemia cooperatively, perhaps as a re sult of bHLH-LIM interactions between their protein products.