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The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia

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The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia Published OnlineFirst September 22, 2010; DOI: 10.1158/1078-0432.CCR-10-0440 Clinical Cancer Molecular Pathways Research The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia David J. Curtis1,2 and Matthew P. McCormack1,2 Abstract T-cell acute lymphoblastic leukemia (T-ALL) is commonly caused by the overexpression of oncogenic transcription factors in developing T cells. In a mouse model of one such oncogene, LMO2, the cellular effect is to induce self-renewal of committed T cells in the thymus, which persist long-term while acquiring additional mutations and eventually giving rise to leukemia. These precancerous stem cells (pre-CSC) are intrinsically resistant to radiotherapy, implying that they may be refractory to conventional cancer therapies. However, they depend on an aberrantly expressed stem cell–like self-renewal program for their maintenance, in addition to a specialized thymic microenvironmental niche. Here, we discuss potential approaches for targeting pre-CSCs in T-ALL by using therapies directed at oncogenic transcription factors themselves, downstream self-renewal pathways, and the supportive cell niche. Clin Cancer Res; 16(23); 5618–23. Ó2010 AACR. Background provide rational approaches for identifying new thera- peutic strategies. T-cell acute lymphoblastic leukemia (T-ALL) is a com- Aberrant expression of the LMO2 gene in T cells accounts mon pediatric leukemia representing approximately 20% for about 9% of T-ALL (4). In addition, activation of LMO2 of all ALL (1). Around half of T-ALL cases harbor recurrent by retroviral insertion was the cause of T-ALL in four chromosomal translocations, leading to aberrant T-cell patients receiving gene therapy for X-linked severe com- expression of a variety of oncogenic transcription factors. bined immunodeficiency (X-SCID; refs. 5–8). In normal The transcription factors most commonly invoved are the hematopoiesis, expression of LMO2 is restricted to adult homeobox genes TLX1 or TLX3, or components of basic hematopoietic stem cells (HSC) and the erythroid lineage, helix-loop helix (bHLH) complexes, including bHLH and is tightly regulated by a network of transcription factors factors themselves (SCL/TAL1, LYL1) and their binding including LMO2 itself, SCL, GATA1, and ETS factors (9). partners, the LIM-domain only (LMO) factors, LMO1 or LMO2 is essential for the formation of yolk sac erythropoi- LMO2 (2). Expression profiling of T-ALL reveals distinct esis, leading to embryonic death at E10.5 (10). In contrast, gene signatures according to the underlying chromoso- LMO2 expression is extinguished early in T-cell develop- mal abnormality, suggesting that the mechanism of ment and is not required for normal development of this leukemogenesis is oncogene specific (3). Despite this lineage (11). In erythroid cells, Lmo2 functions as a brid- genetic heterogeneity, current therapies for both B- and ging molecule assembling a multiprotein transcriptional T-cell ALL are essentially identical, using multidrug com- complex that includes hetero-dimers of E proteins (E47 or binations, prolonged low-dose maintenance chemother- HEB) and Scl or Lyl1, as well as Gata1 and Ldb1 (12). This apy, and allogeneic bone marrow transplant for high-risk complex binds to DNA through the bHLH factors and or relapsed disease. Unfortunately, with this generic GATA1, recognizing a bipartite DNA sequence comprising approach, 20% of children and 50% of adults succumb an E box and a GATA site. This core bHLH-GATA complex to relapsed disease (1). A better understanding of how can act as a repressor or activator of transcription depend- these chromosomal translocations cause leukemia will ing upon the recruitment of other partner proteins, which occurs in a cell stage–specific manner. In a mouse model of Lmo2-induced T-ALL, a different multiprotein complex was identified in the immature À À Authors' Affiliations: 1Rotary Bone Marrow Research Laboratories, Royal CD4 CD8 double negative (DN) T cells of the thymus, Melbourne Hospital; 2Department of Medicine, University of Melbourne, comprising Lmo2, Scl, E47, and Ldb1, which binds to a Parkville, Australia bipartite E-box motif (13). Differing multiprotein com- Corresponding Author: Matthew P. McCormack, Royal Melbourne plexes in normal and T-ALL cells provide a window for Hospital and University of Melbourne, Rotary Bone Marrow Research Laboratories and Department of Medicine, Grattan St, Parkville, Victoria specificity of therapeutics that could disrupt the leukemic 3050, Australia. Phone: 0061-3-9342-7573; Fax: 0061-3-9342-8634; Lmo2 complex, but spare the normal complex that may be E-mail: [email protected] essential for maintenance of HSCs and/or erythropoiesis. doi: 10.1158/1078-0432.CCR-10-0440 Animal models of Lmo2-induced T-ALL provide an Ó2010 American Association for Cancer Research. invaluable tool for understanding the mechanism of 5618 Clin Cancer Res; 16(23) December 1, 2010 Downloaded from clincancerres.aacrjournals.org on October 7, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst September 22, 2010; DOI: 10.1158/1078-0432.CCR-10-0440 Molecular Basis of Lmo2-Induced T-ALL Differentiation pTα Fig. 1. Molecular pathways in block Lmo2-induced self-renewing thymocytes. LMO2-LDB1 forms a Self-renewal bridge between heterodimers of PML E47 and LYL1. This formation body PML leads to repression of T-cell HHEX LMO2 differentiation genes including LDB1 LMO2 pTa, perhaps through loss of E E47 protein dimers. The LMO2 E47 LYL1 LYL1 complex also activates expression STAT 3/5 of the homeodomain protein Survival CATCTG CATCTG HHEX that resides in the nucleolar PML body, and the NF-kB signaling pathway. These changes KIT induce a self-renewal program AKT NFKβ that is restricted to DN3 P thymocytes, which receive PI3K γ-secretase survival and/or proliferation SCF signals such as Notch ligands and DL4 Proliferation SCF from the thymic stroma. Notch1 Self-renewal of these pre-CSCs allows acquisition of other genetic mutations, such as activating mutations of Notch or PI3K Thymic pathways, which may allow the stroma pre-CSCs to expand and escape from their thymic niche. © 20102010 AmericanAmerican AssociationAssociation forfoor Cancer Research leukemogenesis and testing new therapies. Transgenic and reduced E-protein expression in Scl-transgenic mice mice expressing Lmo2 in T cells develop T-ALL, albeit accelerates T-cell leukemogenesis (25, 26). Together, these after a long latency period (14, 15). A similar mouse studies have concluded that the SCL and LMO oncogenes model of T-ALL involves the overexpression of Scl with or induce leukemia by perturbed T-cell differentiation without Lmo1 (16–18). Owing to the similarity between through loss of E-protein function. Lmo1 and Lmo2, and the fact that Scl binds to Lmo2 and Given the multigenic nature of LMO2-induced T-ALL, can accelerate Lmo2-driven leukemogenesis (19, 20), we we reasoned that impaired differentiation would not will consider these models together, although the possi- alone be sufficient for DN thymocytes to acquire the bility remains that distinct molecular mechanisms under- requisite additional genetic mutations. Indeed, blocked lie the two models. In both transgenic models, a delayed T-cell development due to impaired T-cell receptor (TCR) onset of T-ALL is due to the requirement for additional recombination or expression is insufficient to induce genetic mutations, which include activating mutations of T-ALL in mouse models (27). Accordingly, using a com- Notch signaling and loss of the Cdkn2a locus, both of bination of in vivo cell marking and transplantation of which are also observed in LMO2-associated human T- thymocytes from young Lmo2-transgenic mice, we ALL (7, 8, 21–23). have recently shown that the primary cellular effect of To understand the mechanism of leukemogenesis by Lmo2 is to induce self-renewal–committed T cells in the SCL/LMO proteins, a number of groups have examined thymus at the DN3 stage of T-cell development À À À þ the thymi of preleukemic transgenic mice. These studies (CD4 CD8 CD44 CD25 ;ref.28).Thispopulationof reveal a preleukemic phenotype characterized by a small cells has many features of cancer stem cells (CSC), thymus with increased apoptosis and an expanded propor- including the ability to serially transplant, the ability to tion of immature DN T cells (20, 24). Gene expression generate mature T cells, and the expression of a stem cell studies of these preleukemic thymocytes reveal a loss of signature. However, as these self-renewing thymocytes T-cell differentiation genes, most notably the pre–T-cell were evident soon after birth, up to 1 year before overt receptor alpha subunit (pTa; Fig. 1), which is required T-ALL, we refer to them as precancerous stem cells (pre- þ þ for progression of DN T cells to the CD4 CD8 double- CSCs). positive (DP) stage (17). The phenotype of E-protein– Evidence for CSCs in T-ALL is provided by the ability to deficient mice is similar to that of Scl/Lmo-transgenic mice, propagate human T-ALL in NOD-SCID mice (29). Similar www.aacrjournals.org Clin Cancer Res; 16(23) December 1, 2010 5619 Downloaded from clincancerres.aacrjournals.org on October 7, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst September 22, 2010; DOI: 10.1158/1078-0432.CCR-10-0440 Curtis and McCormack to acute myelogenous leukemia and B-cell ALL, CSC activ- essential for the oncogenic function of Lmo2. Secondly, þ À À ity is enriched in the rare CD34 CD4 CD7 subfraction of LMO2 interacts with the Lim domain-binding (LDB) pro- T-ALL (30–32). The CSC hypothesis posits that the stem tein LDB1. The phenotype of Ldb1 knockout mice suggests cell–like properties of CSCs make them more resistant to that it is an essential cofactor for Lmo2 (37). therapies including chemo-radiation. As experimental evi- With regard to targeting LMO2, two successful dence for this hypothesis, we have shown that self-renew- approaches have been recently developed by the Rabbitts ing Lmo2-transgenic thymocytes can survive high-dose laboratory.
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