Lmo2's Oncogenic Function in T-Cell Leukemia Requires Ldb1

Abstract

LIM domain Only-2 (LMO2) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). LMO2 encodes a small protein with 2 LIM domains that is part of a large multiprotein complex in hematopoietic stem and progenitor cells, where it is required for HSC specification and maintenance. Many of LMO2's protein partners in HSPCs are expressed in T-ALL implying that protein complexes similar to those nucleated by LMO2 in HSPCs also play a role in leukemia. In this study, we analyzed a critical component of the LMO2 associated complex, LIM domain binding1 (LDB1). LDB1 appears to be an obligate partner of LMO2 in HSPCs but it is not required for T-cell development from committed progenitors. LDB1 is concordantly expressed with LMO2 in human T-ALL although its expression is more widespread than LMO2. To further define Ldb1's role in leukemia, we induced its conditional knockout in CD2-Lmo2 transgenic mice. CD2-Lmo2 transgenic mice develop T-ALL with high penetrance and closely model the human disease. We discovered that Lmo2-induced T-ALL was markedly attenuated in penetrance and latency by Ldb1 deletion. Since Lmo2 induces a distinct differentiation arrest in T-cell progenitors prior to leukemic transformation, we analyzed the differentiation of T-cell progenitors in CD2-Lmo2 transgenic/floxed-Ldb1/Lck-Cre mice and in non-Lmo2 transgenics: floxed-Ldb1/Lck-Cre mice. Ldb1 deletion by Lck-Cre was efficient in double negative and double positive T-cell progenitors. In striking contrast, Ldb1 deletion could not be induced in CD2-Lmo2 transgenic T-cell progenitors. Consistent with this finding, T-ALLs that developed in CD2-Lmo2/floxed-Ldb1/Lck-Cre mice had incomplete deletion of Ldb1. These results imply that Ldb1 is a required factor for Lmo2 to induce T-ALL. Lastly, gene expression analysis of Lmo2-induced T-ALLs and ChIP-exonuclease analysis of Ldb1 occupancy in T-ALL suggested that the Lmo2/Ldb1 complex enforced a gene signature similar to that seen in HSPCs and in Early T-cell Precursor ALL. In conclusion, Ldb1 is a required partner for Lmo2 to induce T-ALL. Additionally, the HSPC function of Lmo2/Ldb1 complexes may be recapitulated in T-cell progenitors prior to T-ALL. DisclosuresNo relevant conflicts of interest to declare.