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.
Five X-linked severe combined immunodeficiency patients (SCID-X1) successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus subsequently developed T-cell leukemia and four contained insertional mutations at LMO2. Genetic evidence also suggests a role for IL2RG in tumor formation, although this remains controversial. Here, we show that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are similar to those deregulated in human leukemias with high LMO2 expression and are highly predictive of the leukemias induced in SCID-X1 patients. We also provide additional evidence supporting the notion that IL2RG and LMO2 cooperate in leukemia induction but are not sufficient and require additional cooperating mutations. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy.
LIM domain Only 2 (Lmo2) is frequently deregulated in sporadic and gene therapy-induced acute T-cell lymphoblastic leukemia (T-ALL) where its overexpression is an important initiating mutational event. In transgenic and retroviral mouse models, Lmo2 expression can be enforced in multiple hematopoietic lineages but leukemia only arises from T cells. These data suggest that Lmo2 confers clonal growth advantage in T-cell progenitors. We analyzed proliferation, differentiation, and cell death in CD2-Lmo2 transgenic thymic progenitor cells to understand the cellular effects of enforced Lmo2 expression. Most impressively, Lmo2 transgenic T-cell progenitor cells were blocked in differentiation, quiescent, and immortalized in vitro on OP9-DL1 stromal cells. These cellular effects were concordant with a transcriptional signature in Lmo2 transgenic T-cell progenitor cells that is also present in hematopoietic stem cells and Early T-cell Precursor ALL. These results are significant in light of the crucial role of Lmo2 in the maintenance of the hematopoietic stem cell. The cellular effects and transcriptional effects have implications for LMO2-dependent leukemogenesis and the treatment of LMO2-induced T-ALL.
Adult T-cell leukemia/lymphoma (ATLL) is an incurable disease where most patients succumb within the first year of diagnosis. Both standard chemotherapy regimens and mAbs directed against ATLL tumor markers do not alter this aggressive clinical course. Therapeutic development would be facilitated by the discovery of genes and pathways that drive or initiate ATLL, but so far amenable drug targets have not been forthcoming. Because the IL-2 signaling pathway plays a prominent role in ATLL pathogenesis, mutational analysis of pathway components should yield interesting results. In this study, we focused on JAK3, the nonreceptor tyrosine kinase that signals from the IL-2R, where activating mutations have been found in diverse neoplasms. We screened 36 ATLL patients and 24 ethnically matched controls and found 4 patients with mutations in JAK3. These somatic, missense mutations occurred in the N-terminal FERM (founding members: IntroductionATLL is an aggressive T-cell neoplasm that is resistant to diverse therapeutic approaches. Because the disease is rare, small case series have been published testing cytotoxic chemotherapy, IFN therapy, nucleoside analogues, stem cell transplantation, and immune therapy, but no specific regimen induces durable remission. 1 Cures have been reported after stem cell transplantation but the treatment-related morbidity and mortality are high. 2 Unfortunately, newly diagnosed patients can only expect a median survival of Ͻ 12 months. Perhaps through better understanding of the unique biology and pathogenesis of ATLL we could generate novel therapeutic targets. Indeed, ATLL is a remarkable example of retrovirally induced cancer in humans. 3 ATLL is caused by infection of T cells by human T-lymphotropic virus-1 (HTLV-1) which is endemic in southwestern Japan, the Caribbean islands, West Africa, and South America. HTLV-1 is a complex retrovirus that expresses multiple gene products that contribute to T-cell transformation; among these, the retroviral oncogene tax can induce T-cell immortalization on its own and is thought to be absolutely required for ATLL development. [4][5][6] Interestingly, ATLL arises in only 5% of patients infected with HTLV-1 and disease presents up to 3 decades after initial infection. This suggests that there are probably multiple oncogenic mutations from the initiating hit of HTLV-1 infection to the development of ATLL. In fact, host somatic mutations in specific genes and pathways are probably required for ATLL and could explain the low penetrance and long latency.One major pathway implicated in ATLL development is the activation of IL-2 (and related cytokines) signaling. 3,7,8 In fact, the IL2 and IL2RA (␣ chain or CD25) genes are trans-activated by tax protein. 9 The IL-2R and IL-2R␥ chains are constitutively expressed on T cells but the high-affinity IL-2R requires the IL-2R␣ chain. 10 Thus, tax-expressing T cells are induced to proliferate because of autocrine signaling from IL-2 to the IL-2R, composed of ␣, , ␥ chains; other HTLV-1 gene products may contri...
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