Ldb1 is required for Lmo2 oncogene–induced thymocyte self-renewal and T-cell acute lymphoblastic leukemia

Abstract

Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell acute lymphoblastic leukemia (T-ALL), designated early T-cell precursor ALL, which is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. It has been suggested that Lmo2 exerts these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors; however, direct experimental evidence for this mechanism is lacking. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in an Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in Lmo2-induced thymocyte self-renewal and thymocyte radiation resistance and for the transition of preleukemic thymocytes to overt T-ALL. Moreover, Ldb1 was also required for acquisition of the aberrant preleukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Co-binding of Ldb1 and Lmo2 was detected at the promoters of key upregulated T-ALL driver genes (Hhex, Lyl1, and Nfe2) in preleukemic Lmo2 transgenic thymocytes, and binding of both Ldb1 and Lmo2 at these sites was reduced following Cre-mediated deletion of Ldb1. Together, these results identify a key role for Ldb1, a nonproto-oncogene, in T-ALL and support a model in which Lmo2-induced T-ALL results from failure to downregulate Ldb1/Lmo2-nucleated transcription complexes which normally function to enforce self-renewal in bone marrow hematopoietic progenitors.

Key sunitinib‐related biomarkers for renal cell carcinoma

“…HAMP has a strong correlation with immune and carcinoma. Studies concerned about LYL1 mainly focused on lymphoblastic leukemia which indicated LYL1 acted as a oncogene in acute lymphoblastic leukemia and induced the development and progression of acute lymphoblastic leukemia 65–69 and LYL1 has been demonstrated to regulate the early lymphoid differentiation of immature hematopoietic cells, 70 which suggested it is possible for the association between immune infiltration and LYL1 in ccRCC.…”

Multi-modular structure of the gene regulatory network for specification and commitment of murine T cells

“…Although data for cells in the same developmental stages with complete disruption of Ikaros ( Ikzf1 ) were not available, differentially expressed genes that responded to Ikaros ( Ikzf1 ) zinc finger 4 deletion were also added ( 85 ). Finally, we included data from studies of acute gain of function of factors at stages after they would normally have been shut down, including PU.1 ( Spi1 ) ( 48 ), and the transcription factor adaptor Lmo2 ( 86 – 88 ). In addition, supporting results came from studies introducing into pro-T cells acute antagonists of key transcription factors, including the natural E protein antagonist ID2 ( 89 ) or an artificially constructed dominant repressor form of PU.1 ( 90 ).…”

“…However, overexpression of Lmo2 or Lyl1 in thymocytes does not drive the T cell program. Instead, it causes T-cell lymphoma/leukemia, and when Lmo2 is involved, it causes increased expression of genes associated with progenitor fates ( 86 – 88 , 201 – 203 )( Figures 4B, C , top). Under these conditions, the Lmo2/Lyl1 protein complex directly activates Hhex , which upregulates Kit expression (encoding the growth factor receptor cKit) and promotes self-renewal ( 91 ) at the expense of T-lineage differentiation.…”

“…Other factors expressed during the Phase 1 period could also contribute important regulatory inputs to targets in the stem/progenitor module, including Mef2c, Meis1, Hoxa9, Etv6, Hhex, and Mycn. These are all implicated in T-ALL (reviewed in ( 205 )), similarly to Lyl1 and Lmo2 ( 86 – 88 , 91 ), but are not yet adequately explored in the normal pro-T cell context. Hoxa9 is implicated in generating lymphoid-competent multipotent precursors ( 206 ) and has been reported to synergize with Runx1 to drive induced pluripotent cells towards a T cell pathway ( 207 ).…”

LIM-Domain-Binding Protein 1 Mediates Cell Proliferation and Drug Resistance in Colorectal Cancer

“…So far, some papers have reported the functions and roles of LDB1 in several tumors. For example, in the proto-oncogene LMO2-induced T-cell acute lymphoblastic leukemia, LMO2 along with LDB1, b-HLH and GATA formed a multi-subunit transcription complex, which was required for the oncogenic transformation of immature thymocytes ( 10 ). Another paper also confirmed that LDB1 enhanced the stability of direct and indirect oncoprotein partners in leukemia, such as LMO2 ( 11 ).…”