The protein products of proto‐oncogenes implicated in T cell acute lymphoblastic leukemia include two distinct families of presumptive transcription 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 exceptional homology in their bHLH sequences. We have found that RBTN1 and RBTN2 have the ability to interact with each of the leukemogenic bHLH proteins (TAL1, TAL2 and LYL1). These interactions occur in vivo and appear to be mediated by sequences within the LIM and bHLH domains. The LIM‐bHLH interactions are highly specific in that RBTN1 and RBTN2 will associate with TAL1, TAL2 and LYL1, but not with other bHLH proteins, including E12, E47, Id1, NHLH1, AP4, MAX, MYC and MyoD1. Moreover, RBTN1 and RBTN2 can interact with TAL1 polypeptides that exist in assembled bHLH heterodimers (e.g. TAL1‐E47), suggesting that the RBTN proteins can influence the functional properties of TAL1. Finally, we have identified a subset of leukemia patients that harbor tumor‐specific rearrangements of both their RBTN2 and TAL1 genes. Thus, the activated alleles of these genes may promote leukemia cooperatively, perhaps as a result of bHLH‐LIM interactions between their protein products.

Chromosomal translocations in T-cell acute leukemias can activate genes encoding putative transcription factors such as the LIM proteins RBTN1 and RBTN2 and the DNA-binding basic helix-oop-helix transcription factor TALl associated with T-cell acute lymphocytic leukemia. While not expressed in normal T cells, RBTN2 and TALl are coexpressed in erythroid cells and are both important for erythroid differentiation. We demonstrate, using anti-RBTN2 and anti-TALl antisera, that the LIM protein RBTN2 is not phosphorylated and is complexed with the TALl phosphoprotein in the nucleus of erythroid cells. A complex containing both RETNi and TALl also occurs in a T-cell acute leukemia cell line. Since both RBTN2 and TALl are crucial for normal erythropolesis, these data have important implications for transcription networks therein. Further, since both proteins can be involved in leukemogenesis, these data provide a direct link between proteins activated by chromosomal translocations in T-cell acute leukemia.Chromosomal translocations in T-cell acute leukemias are diverse even though this disease is homogeneous in clinical pattern and histological characteristics. Genes activated by these chromosomal abnormalities have been identified and their protein products shown to be putative transcription factors (1, 2). These genes, which may act as master genes (2), include the basic helix-loop-helix (bHLH) gene TALI formerly called TCL5 and SCL), activated by translocation t(1;14) (3-5), and RBTN1 (also called TTG-l) (6-9) and RBTN2 (formerly called RBTNLI and also called TTG-2) (10-12), which are activated by distinct t(11;14) translocations and which cause T-cell lymphomas in transgenic mice (refs. 13 and 14; and R.

AIBSTRACTThe RBTN2 LIM-domain protein, originally identified as an oncogenic protein in human T-cell leukemia, is essential for erythropoiesis. A possible role for RBTN2 in transcription during erythropoiesis has been investigated. Direct interaction of the RBTN2 protein was observed in vivo and in vitro with the GATAI or -2 zinc-finger transcription factors, as well as with the basic helix-loop-helix protein TALl. By using mammalian two-hybrid analysis, complexes involving RBTN2, TAL1, and GATA1, together with E47, the basic helix-loop-helix heterodimerization partner of TAL1, could be demonstrated. Thus, a molecular link exists between three proteins crucial for erythropoiesis, and the data suggest that variations in amounts of complexes involving RBTN2, TAL1, and GATAl could be important for erythroid differentiation.