Functional interactions between Lmo2, the Arf tumor suppressor, and Notch1 in murine T-cell malignancies

Division of Experimental Hematology, Department of Hematology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(20):5453-62. DOI: 10.1182/blood-2010-09-309831
Source: PubMed


LMO2 is a target of chromosomal translocations in T-cell tumors and was activated by retroviral vector insertions in T-cell tumors from X-SCID patients in gene therapy trials. To better understand the cooperating genetic events in LMO2-associated T-cell acute lymphoblastic leukemia (T-ALL), we investigated the roles of Arf tumor suppressor loss and Notch activation in murine models of transplantation. Lmo2 overexpression enhanced the expansion of primitive DN2 thymocytes, eventually facilitating the stochastic induction of clonal CD4(+)/CD8(+) malignancies. Inactivation of the Arf tumor suppressor further increased the self-renewal capacity of the primitive, preleukemic thymocyte pool and accelerated the development of aggressive, Lmo2-induced T-cell lympholeukemias. Notch mutations were frequently detected in these Lmo2-induced tumors. The Arf promoter was not directly engaged by Lmo2 or mutant Notch, and use of a mouse model in which activation of a mutant Notch allele depends on previous engagement of the Arf promoter revealed that Notch activation could occur as a subsequent event in T-cell tumorigenesis. Therefore, Lmo2 cooperates with Arf loss to enhance self-renewal in primitive thymocytes. Notch mutation and Arf inactivation appear to independently cooperate in no requisite order with Lmo2 overexpression in inducing T-ALL, and all 3 events remained insufficient to guarantee immediate tumor development.

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Available from: Louise M. Treanor, Mar 12, 2014
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    • "Hence, deregulated LMO2 expression is an early mutational event in T-ALL. This is demonstrated in mouse models like bone marrow chimeras and transgenic mice where Lmo2 expression is enforced from constitutive promoters[3],[10]. We identified Lmo2 as a frequent integration site in AKXD mice where retroviral integration analysis and gene expression proved to be informative in modeling gene therapy-induced T-ALLs [11], [12]. "
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    ABSTRACT: The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype.
    PLoS ONE 01/2014; 9(1):e85883. DOI:10.1371/journal.pone.0085883 · 3.23 Impact Factor
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    • "To determine whether these IL7R mutations are oncogenic drivers in ETP-ALL, DN thymocytes from Arf / mice were transduced with MSCV vectors that expressed murine homologues of either of two IL7R mutations identified in human ETP-ALL, IL7R-241-242TC and IL7R-GCinsL243 (Zhang et al., 2012). When these transduced thymocytes were cultured on OP9-DL1 stromal cells, the Il7r mutants caused a partial block at the DN2 stage (Fig. 1 A), similar to the block seen with enforced expression of the Lmo2 transcription factor (Larson et al., 1995; Neale et al., 1995; Treanor et al., 2011). These results show that these mutant Il7r receptors induce a block in differentiation early in thymocyte development and at a stage before irreversible commitment to the T cell lineage. "
    S. Fong ·

    Journal of Experimental Medicine 09/1978; 148(3):817-822. DOI:10.1084/jem.148.3.817 · 12.52 Impact Factor
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    ABSTRACT: NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2012; 26(9):2069-78. DOI:10.1038/leu.2012.116 · 10.43 Impact Factor
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