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Peter D Aplan - One of the best experts on this subject based on the ideXlab platform.

  • Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes
    Genes & development, 2010
    Co-Authors: Mathieu Tremblay, Sabine Herblot, Peter D Aplan, Cedric S. Tremblay, Josée Hébert, Claude Perreault, Trang Hoang
    Abstract:

    Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL. All tumor cells harness identical and specific Notch1 mutations and Tcrb clonal signature, indicative of clonal dominance and concurring with the observation that Notch1 gain of function confers a selective advantage to SCL-LMO1 transgenic thymocytes. Accordingly, a hyperactive Notch1 allele accelerates leukemia onset induced by SCL-LMO1 and bypasses the requirement for pre-TCR signaling. Finally, the time to leukemia induced by the three transgenes corresponds to the time required for clonal expansion from a single leukemic stem cell, suggesting that SCL, LMO1, and Notch1 gain of function, together with an active pre-TCR, might represent the minimum set of complementing events for the transformation of susceptible thymocytes.

  • Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets.
    Leukemia, 2007
    Co-Authors: Ying-wei Lin, Peter D Aplan
    Abstract:

    We compared the gene expression pattern of thymic tumors from precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) that arose in transgenic mice that overexpressed SCL, LMO1 or NUP98-HOXD13 (NHD13) with that of thymocytes from normal littermates. Only two genes, Ccl8 and Mrpl38, were consistently more than fourfold overexpressed in pre-T LBL from all three genotypes analyzed, and a single gene, Prss16 was consistently underexpressed. However, we identified a number of genes, such as Cfl1, Tcra, Tcrb, Pbx3, Eif4a, Eif4b and Cox8b that were over or under-expressed in pre-T LBL that arose in specific transgenic lines. Similar to the situation seen with human pre-T LBL, the SCL/LMO1 leukemias displayed an expression profile consistent with mature, late cortical thymocytes, whereas the NHD13 leukemias displayed an expression profile more consistent with immature thymocytes. We evaluated two of the most differentially regulated genes as potential therapeutic targets. Cfl1 was specifically overexpressed in SCL-LMO1 tumors; inactivation of Cfl1 using okadaic acid resulted in suppression of leukemic cell growth. Overexpression of Ccl8 was a consistent finding in all three transgenic lines, and an antagonist for the Ccl8 receptor-induced death of leukemic cell lines, suggesting a novel therapeutic approach.

  • Identification of Oncogenic Pathways of T-Acute Lymphoblastic Leukemia (T-ALL) through Gene Expression Profiling of Mouse Tumor Models.
    Blood, 2006
    Co-Authors: Maria Luisa Sulis, Peter D Aplan, Neal G. Copeland, Teresa Palomero, Pedro J. Real, Kelly Barnes, Dave Utpal, Fotini Gounari, Gerald Grosveld, Dietmar J. Kappes
    Abstract:

    Transgenic mouse models of T-cell oncogenes such as TAL1 and LMO1, have confirmed their critical role in the development of T-lymphoblastic lymphoma (T-LL). In addition, retroviral insertional mutagenesis (RIM) in mice is a powerful system for the identification of genes involved in T-cells leukemogenesis. However, incomplete knowledge of the pathogenesis of T-ALL limits the ability to stratify patients and to deliver tailored therapy accordingly. Thus, a major goal is to identify common oncogenic pathways downstream of T-cell oncogenes that can serve as therapeutic targets for the treatment of T-ALL. We hypothesize that T-cell oncogenes operate through a limited number of oncogenic pathways with distinct gene expression profiles. Furthermore, we propose that gene expression profiling of murine models of T-cell lymphomas, which harbor specific genetic lesions, will serve to identify such oncogenic pathways and to establish a molecular classification of T-ALL. To test this hypothesis we have analyzed normal thymus and mouse T-cell lymphomas originated from retroviral insertional mutagenesis (n=11) and transgenic and knock-outs models (n=30) using Affymetrix 430A2.0 microarrays. Unsupervised analysis clearly distinguishes tumor samples from normal thymus and clusters the tumors into three major groups. TAL1, LMO2 and E2 proteins are known to be part of a transcriptional complex and to cooperate in T-cell leukemogenesis by suppressing E2A function. Accordingly, mouse tumors originating in TAL1, TAL1/LMO2 transgenic and E2A knock-out mice share a common gene expression signature and cluster together. Supervised analysis of tumors generated by retroviral mutagenesis showed increased expression of the proviral tagged genes and identified corresponding known downstream targets. Nearest neighbor analysis identified high levels of Notch1 expression in tumors with proviral insertion in the Notch1 locus and in tumors generated in the TAL1/, TAL1/LMO2, OLIG2/LMO1, ThPOK and Ikaros mouse models, which harbored activating mutations in NOTCH1. Our results demonstrate that gene expression profiling identifies common oncogenic pathways in T-cell tumors generated in mice, establishes common mechanisms of transformation for several T-ALL oncogenes and allows coupling of poorly characterized genes identified in proviral insertional sites with well characterized oncogenes and downstream molecular pathways. The identification of mechanisms of T-cell transformation common to tumors of different origin lays the ground for the identification of new therapeutic targets for the treatment of T-ALL.

  • Acquired Notch1 Mutations in Murine Precursor-T Leukemia/Lymphoma Models.
    Blood, 2005
    Co-Authors: Ying-wei Lin, Rebecca A. Nichols, John J. Letterio, Peter D Aplan
    Abstract:

    NOTCH1 has been implicated in hematopoiesis, T-cell differentiation, and the pathogenesis of precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). Although rare patients with pre-T LBL have chromosomal translocations that activate NOTCH1 , it has recently been shown that over 50% of human pre-T LBL samples which did not have chromosomal aberrations involving NOTCH1 had activating mutations in the NOTCH1 heterodimerization (HD) and/or the PEST domain. We examined murine pre-T LBL cell lines as well as primary thymic tumors that arose in SCL/LMO1, OLIG2, OLIG2/LMO1, LMO1, NUP98/HOXD13 transgenic mice, and [ p27 (− /−) / SMAD3 (−/+)] mice for evidence of Notch1 mutations. We also investigated the timing of Notch1 mutation in SCL/LMO1 transgenic mice. We found that 13/19 cell lines and 29/49 primary thymic tumors had Notch1 mutations in either the HD or PEST domain, but not both. Of the thirteen cell lines with Notch1 mutations, twelve had mutations in the PEST domain. The cell lines with Notch1 mutations were sensitive to gamma-secretase inhibitor treatment, indicating that the mutations were important for the survival of these cells. Of twenty-nine tumors with Notch1 mutations, 23 were in the PEST domain and 6 in the HD. All HD mutations were single base substitutions, whereas all PEST domain mutations were insertion/deletion mutations. Intriguingly, half of the PEST domain mutations mapped to one of two mutational hot spots, suggesting that these regions may be prone to insertion/deletion mutations. Thymocytes from clinically healthy SCL/LMO1 mice aged 5 weeks showed evidence of oligoclonal T-lymphocyte expansion, but did not have Notch1 mutations and did not form tumors when injected into nude mice (pre-malignant thymocytes), whereas thymocytes from SCL/LMO1 mice aged 8–12 weeks had Notch1 mutations and formed tumors upon transplantation into nude mice. Thus, Notch1 mutations are very frequent secondary events that can cooperate with a wide range of primary events as cells progress from a pre-malignant to a fully transformed state.

  • Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma.
    Blood, 2005
    Co-Authors: Ying-wei Lin, Rebecca A. Nichols, John J. Letterio, Peter D Aplan
    Abstract:

    NOTCH1 is frequently mutated in human precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). In the current study, we found that 13 of 19 cell lines and 29 of 49 primary tumors from SCL/LMO1, OLIG2/LMO1, OLIG2, LMO1, NUP98/HOXD13, and p27-/-/SMAD3+/- mice had Notch1 mutations in either the heterodimerization (HD) or the glutamic acid/serine/threonine (PEST) domain but not both. Thymocytes from clinically healthy SCL/LMO1 mice aged 5 weeks did not have Notch1 mutations, whereas thymocytes from clinically healthy SCL/LMO1 mice aged 8 to 12 weeks did have Notch1 mutations and formed tumors upon transplantation into nude mice. Remarkably, all of the HD domain mutations that we identified were single-base substitutions, whereas all of the PEST domain mutations were insertions or deletions, half of which mapped to 1 of 2 mutational “hot spots.” Taken together, these findings indicate that Notch1 mutations are very frequent events that are acquired relatively early in the process of leukemic transformation and are important for leukemic cell growth. (Blood. 2006;107: 2540-2543)

David S. Chervinsky - One of the best experts on this subject based on the ideXlab platform.

  • scid Thymocytes with TCRβ Gene Rearrangements Are Targets for the Oncogenic Effect of SCL and LMO1 Transgenes
    Cancer research, 2001
    Co-Authors: David S. Chervinsky, Du H. Lam, Kenneth W. Gross, Michael P. Melman, Peter D Aplan
    Abstract:

    SCL and LMO1 were both discovered by virtue of their activation by chromosomaltranslocation in patients with T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of SCL and LMO1 in the thymus of transgenic mice leads to T-ALL at a young age. scid (severe combined immunodeficient) mice are unable to efficiently recombine antigen receptor genes and consequently display a developmental block at the CD4-CD8- to CD4+CD8+ transition. To test the hypothesis that this developmental block would protect SCL / LMO1 transgenic mice from developing T-ALL, we crossed the SCL and LMO1 transgenes onto a scid background. The age of onset for T-ALL in the SCL / LMO1 / scid mice was significantly delayed ( P < 0.001) compared with SCL / LMO1 / wild-type mice. Intriguingly, all of the SCL / LMO1 / scid malignancies displayed clonal, in-frame TCRβ gene rearrangements. Taken together, these findings suggest that the “leaky” scid thymocyte that undergoes a productive TCRβ gene rearrangement is susceptible to the oncogenic action of SCL and LMO1 and additionally suggests that TCRβ gene rearrangements may be required for the oncogenic action of SCL and LMO1 .

  • Development and characterization of T cell leukemia cell lines established from SCL/LMO1 double transgenic mice.
    Leukemia, 2001
    Co-Authors: David S. Chervinsky, Xian-feng Zhao, D H Lam, Peter D Aplan
    Abstract:

    Development and characterization of T cell leukemia cell lines established from SCL / LMO1 double transgenic mice

  • development and characterization of t cell leukemia cell lines established from scl LMO1 double transgenic mice
    Leukemia, 2001
    Co-Authors: David S. Chervinsky, Xian-feng Zhao, Michael P. Melman, D H Lam, Peter D Aplan
    Abstract:

    Development and characterization of T cell leukemia cell lines established from SCL / LMO1 double transgenic mice

  • Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice.
    Molecular and cellular biology, 1999
    Co-Authors: David S. Chervinsky, Xian-feng Zhao, Du H. Lam, Marykay Ellsworth, Kenneth W. Gross, Peter D Aplan
    Abstract:

    The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms of proliferation, apoptosis, clonality, and immunophenotype prior to the onset of a frank malignancy. At 4 weeks of age, thymocytes from SCL LMO1 mice show 70% fewer total thymocytes, with increased rates of both proliferation and apoptosis, than control thymocytes. At this age, a clonal population of thymocytes begins to populate the thymus, as evidenced by oligoclonal T-cell-receptor gene rearrangements. Also, there is a dramatic increase in immature CD44+ CD25− cells, a decrease in the more mature CD4+ CD8+ cells, and development of an abnormal CD44+ CD8+ population. An identical pattern of premalignant changes is seen with either a full-length SCL protein or an amino-terminal truncated protein which lacks the SCL transactivation domain, demonstrating that the amino-terminal portion of SCL is not important for leukemogenesis. Lastly, we show that the T-ALL which develop in the SCL LMO1 mice are strikingly similar to those which develop in E2A null mice, supporting the hypothesis that SCL exerts its oncogenic action through a functional inactivation of E proteins.

Trang Hoang - One of the best experts on this subject based on the ideXlab platform.

  • SCL/TAL1 in Hematopoiesis and Cellular Reprogramming.
    Current topics in developmental biology, 2016
    Co-Authors: Trang Hoang, Martin R
    Abstract:

    SCL, a transcription factor of the basic helix-loop-helix family, is a master regulator of hematopoiesis. Scl specifies lateral plate mesoderm to a hematopoietic fate and establishes boundaries by inhibiting the cardiac lineage. A combinatorial interaction between Scl and Vegfa/Flk1 sets in motion the first wave of primitive hematopoiesis. Subsequently, definitive hematopoietic stem cells (HSCs) emerge from the embryo proper via an endothelial-to-hematopoietic transition controlled by Runx1, acting with Scl and Gata2. Past this stage, Scl in steady state HSCs is redundant with Lyl1, a highly homologous factor. However, Scl is haploinsufficient in stress response, when a rare subpopulation of HSCs with very long term repopulating capacity is called into action. SCL activates transcription by recruiting a core complex on DNA that necessarily includes E2A/HEB, GATA1-3, LIM-only proteins LMO1/2, LDB1, and an extended complex comprising ETO2, RUNX1, ERG, or FLI1. These interactions confer multifunctionality to a complex that can control cell proliferation in erythroid progenitors or commitment to terminal differentiation through variations in single component. Ectopic SCL and LMO1/2 expression in immature thymocytes activates of a stem cell gene network and reprogram cells with a finite lifespan into self-renewing preleukemic stem cells (pre-LSCs), an initiating event in T-cell acute lymphoblastic leukemias. Interestingly, fate conversion of fibroblasts to hematoendothelial cells requires not only Scl and Lmo2 but also Gata2, Runx1, and Erg, indicating a necessary collaboration between these transcription factors for hematopoietic reprogramming. Nonetheless, full reprogramming into self-renewing multipotent HSCs may require additional factors and most likely, a permissive microenvironment.

  • lmo2 regulates dna replication in hematopoietic cells
    Blood, 2015
    Co-Authors: Marie Claude Sincennes, Magali Humbert, Benoit Grondin, Christophe Cazaux, Veronique Lisi, Nazar Mashtalir, E Bachir L Affar, Alain Verreault, Trang Hoang
    Abstract:

    Oncogenic transcription factors are major drivers in acute leukemias. These oncogenes are believed to subvert normal cell identity via the establishment of gene expression programs that dictate cell differentiation and growth. The LMO2 oncogene, which is commonly activated in T-cell acute lymphoblastic leukemia (T-ALL), has a well-established function in transcription regulation. We and others previously demonstrated that LMO1 or LMO2 collaborate with the SCL transcription factor to activate a self-renewal program that converts non self-renewing progenitors into pre-leukemic stem cells. Here we demonstrate a non-transcriptional role of LMO2 in controlling cell fate by directly promoting DNA replication, a hitherto unrecognized mechanism that might also account for its oncogenic properties. To address the question whether LMO2 controls other functions via protein-protein interactions, we performed a proteome-wide screen for LMO2 interaction partners in Kit+ Lin- cells. In addition to known LMO2-interacting proteins such as LDB1 and to proteins associated with transcription, we unexpectedly identified new interactions with three essential DNA replication enzymes, namely minichromosome 6 (MCM6), DNA polymerase delta (POLD1) and DNA primase (PRIM1). First, we show that in Kit+ hematopoietic cells (TF-1), all components of the pre-replication complex co-immunoprecipitate with LMO2 but not with SCL, suggesting a novel SCL-independent function. Second, LMO2 is recruited to DNA replication origins in these cells together with MCM5. Third, tethering LMO2 to synthetic DNA sequences is sufficient to transform these into origins of replication. Indeed, we show by DNA capture that LMO2 fused to the DNA binding domain of GAL4 is sufficient to recruit DNA replication proteins to GAL4 binding sites on DNA. In vivo , this recruitment is sufficient to drive DNA replication in a manner which is dependent on the integrity of the GAL4 binding sites. These results provide unambiguous evidence for a role of LMO2 in directly controlling DNA replication. Cell cycle and cell differentiation are tightly coordinated during normal hematopoiesis, both during erythroid differentiation and during thymocyte development. We next addressed the functional importance of LMO2 in these two lineages. Erythroid cell differentiation proceeds through different stages from the CD71+Ter119- to the CD71-Ter119+. These stages are also distinguishable by morphological criteria. We observe that LMO2 protein levels directly correlate with the proportion of cells in S phase, i.e. both LMO2 levels and the proportions of cycling cells decrease with terminal erythroid differentiation. Strikingly, lowering LMO2 levels in fetal liver erythroid progenitors via shRNAs decreases the proportion of cells in S phase and arrests Epo-dependent cell growth. Despite a drastic decrease in the numbers of erythroid precursors, these cells differentiate readily to the CD71-Ter119+ stage. Therefore, LMO2 levels dictate cell fate in the erythroid lineage, by favoring DNA replication at the expense of terminal maturation. Conversely, ectopic expression in thymocytes induces DNA replication and drives cells into cell cycle, causing differentiation blockade. Our results define a novel role for the oncogenic transcription factor LMO2 in directly promoting DNA synthesis. To our knowledge, this is the first evidence for a non-transcriptional function of the LMO2 oncogene that drives cell cycle at the expense of differentiation, favouring progenitor cell expansion in the thymus, and causing T-ALL when ectopically expressed in the T lineage. We propose that the non-transcriptional control of DNA replication uncovered here for LMO2 may be a more common function of oncogenic transcription factors than previously appreciated. Disclosures No relevant conflicts of interest to declare.

  • Modelling acute leukemias in mice: clonal evolution and the emergence of leukemic stem cells.
    BMC Proceedings, 2013
    Co-Authors: Bastien Gerby, Trang Hoang
    Abstract:

    The concept of cancer stem cells (CSCs) is based on a hierarchic model of cancer whereby cells within a tumour exhibit distinct biological characteristics and only CSCs are able to grow indefinitely and to maintain the neoplastic process. The molecular and cellular characteristics of CSCs are thought to be due to genetic and epigenetic states reminiscent of those normal stem cells. Precisely, cancer arise from the neoplastic transformation of stem cells or committed-progenitor cells [1] through two types of events. First, normal stem cells can acquire genetic alterations that alter its growth control, increase its resistance to apoptosis and interfere with cell differentiation. Second, non-stem cells can be altered by the oncogenic process to reacquire the self-renewal properties of normal stem cells. In both cases, these characteristics confer a particular resistance to drugs, implying that CSCs are involved in the persistence of tumour cells during treatment and consequently, are responsible of relapses. The concept of CSCs has come from pioneering studies on acute myeloid leukemia (AML) which have defined a distinct subpopulation of tumour cells, the leukemia initiating cells (LICs), characterized by their capacity to initiate the disease when transplanted into imuno-deficient mice [2,3]. A confounding issue in the field has been the equation of CSCs with the cell of origin of acute leukemias. Indeed, these original studies and subsequent work suggested that AML derived from the malignant transformation of hematopoietic stem cells (HSCs) [4,5]. However, growing evidence based on cellular and molecular studies led to the recognition that the cell of origin of AML is a committed progenitor that normally lack any potential for self-renewal [6,7]. This controversy may be reconciled by assuming that AMLs may represent in some cases a stem cell disorder, while in other cases, the reacquisition of stem cell characteristics by a committed progenitor [8]. The situation is different in paediatric acute lymphoblastic leukemia (ALL), where there is evidence that leukemia initiating activity is observed not only in the immature cell population but also in populations corresponding to a range of normal precursor cells [9,10]. Precisely, the analysis of leukemic and pre-leukemic stem cell populations in a pair of identical twins indicate that the putative stem cell responsible for initiating and maintaining B-ALL are not a fixed cell identity but evolve both in genotype and phenotype [11]. Comforting this observation, a process of clonal evolution at the level of LIC populations was provided both in B-ALL and T-ALL. Indeed, the molecular investigation of individual LIC helped to establish a complex clonal architecture of individual leukemia, showing that LIC are genetically heterogeneous due to the process of clonal evolution [12-14]. T-acute lymphoblastic leukemia (T-ALL) represents about 15% of paediatric leukemias. Several studies in these last years have, in part, elucidated the molecular mechanism of T-ALL transformation. Indeed, T-leukemogenesis is a multi-step process characterized by the acquisition of several oncogenic events. Especially, genes encoding the SCL transcription factor and its nuclear partners LMO1 and LMO2 are frequently deregulated in T-ALL. Furthermore, activating mutations of NOTCH1 are found in more than 50% of T-ALL cases, and are frequently associated with chromosomal abnormalities in the SCL and/or LMO1/2 locus [15,16], implying that these mutational events frequently collaborate during neoplastic transformation of thymocytes. It was originally proposed that the phenotype of the tumor reflects the cell of origin of T-ALL [17]. However, recent studies indicate that fully transformed T-leukemic cells are functionally heterogeneous and may originate from the leukemic transformation of an early T-cell progenitor [18,19]. Furthermore, it has been recently shown that the overexpression of the LMO2 oncogene in the thymus induce the emergence of a pre-leukemic stem cell (pre-LSC) population [20] but the identification of the cell of origin of T-ALL and the mechanisms by which these oncogenes reprogram normal thymocytes to become T-LIC remain unclear. We took advantage of a transgenic mouse model that closely reproduces paediatric T-ALL to define oncogenic events during the pre-leukemic phase. We show that SCL-LMO1 inhibit thymocyte differentiation at the double negative to double positive transition, via inhibition of two transcription factors that are essential in the thymus, HEB and E2A [21,22]. Moreover, SCL-LMO1 reprograms thymocyte progenitors to confer abnormal self-renewal capacity. The acquisition of stem cell-like properties establishes a pre-leukemic state in thymocytes by causing an expansion of the CD4-CD8- double negative (DN) population of progenitors that actively proliferate under the influence of the pre-TCR and are therefore at risk of acquiring mutations. Strikingly, our data indicate that the pre-TCR favors the acquisition of Notch1 mutations in SCL-LMO1 pre-leukemic stem cells [23]. Finally, SCL, LMO1 and NOTCH1 together induce a polyclonal disease in transgenic mice, which is comparable to that induced by transplantation of a single leukemic stem cell. We therefore conclude that these three oncogenes are sufficient to transform DN thymocytes. In summary, we show that in T-ALL, the target cell of transformation by the SCL-LMO1 oncogenes are double negative thymocytes that acquire aberrant self-renewal activities but remain non-leukemogenic. Acquisition of activating Notch1 mutations then transforms these thymocyte progenitors into leukemic stem cells [23].

  • Thymocyte Reprogramming by the Scl, LMO1 and Notch1 Oncogenes
    Blood, 2012
    Co-Authors: Bastien Gerby, Cedric S. Tremblay, Mathieu Tremblay, Shanti Rojas-sutterlin, Trang Hoang
    Abstract:

    Abstract 207 Normal thymic progenitors are devoid of self-renewal capacity, which is a distinctive stem cell property. These thymic progenitors progress into the thymus through several stages of differentiation (DN1, DN2-4, DP) before giving rise to CD4 + or CD8 + immunocompetent cells that are released into the periphery. Therfore, thymic output requires continuous seeding from stem cell-derived progenitors. T cell acute lymphoblastic leukemia (T-ALL) is a common cancer in children. Almost 25% of childhood T-ALL involve the SCL transcription factor and/or its nuclear partners LMO1/2 and more than 50% harbour gain of function mutations of NOTCH1 . Using a transgenic mouse model that reproduces the human disease, we previously showed that activation of SCL , LMO1 and Notch1 in the thymus is sufficient to transform thymocyte progenitors and induce T-ALL ( Tremblay M et al., 2010 ). Here, we explore the mechanism of transformation by these three oncogenes in primary thymocytes during the pre-leukemic stage. Our results indicate that the SCL and LMO1 oncogenes collaborate to confer an aberrant self-renewal potential to a subset of pre-leukemic thymocytes, via induction of a stem cell gene signature that also distinguishes primary T-ALL patient samples in which LMO2 is expressed. Furthermore, our clonality and functional analyses indicate that only a few clones of preleukemic thymocytes from Scl-LMO1 mice are able to colonize the thymus of recipient mice in transplantation assays and produce mature T-cells during the pre-leukemic stage. Precisely, we show that self-renewal activity is enriched in DN3 thymocytes which eventually acquire Notch1 gain of function mutations and leukemia initiating activity. On the other hand, the Notch1 oncogene by itself does not confer self-renewal properties to thymocytes. Rather, we show that the Notch1 oncogene enhances the activity of the SCL-LMO1 oncogene to increase the frequency of pre-Leukemic Stem Cells (pre-LSCs) without modifying the clonal expansion of individual pre-LSC when transplanted at limiting dilutions. These results indicate that the Notch1 oncogene modifies the self-renewal activity enforced by the SCL tg LMO1 tg oncogenes into a self-renewal of expansion, typical of a transformed state. Furthermore, NOTCH1 confers an invasive potential to SCL tg LMO1 tg thymocytes that become thymus-independent and acquire the capacity to develop in peripheral organs. Therefore, our observations are consistent with the view that the SCL-LMO1 oncogenic transcription factors reprogram DN3 thymocytes to acquire self-renewal potential, thereby establishing a pre-leukemic state. Finally, NOTCH1 activation provides a strong signal that collaborates with the SCL-LMO1 oncogenes to induce T-ALL by favoring self-renewal divisions in pre-LSC together with an invasive capacity. Disclosures: No relevant conflicts of interest to declare.

  • Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes
    Genes & development, 2010
    Co-Authors: Mathieu Tremblay, Sabine Herblot, Peter D Aplan, Cedric S. Tremblay, Josée Hébert, Claude Perreault, Trang Hoang
    Abstract:

    Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL. All tumor cells harness identical and specific Notch1 mutations and Tcrb clonal signature, indicative of clonal dominance and concurring with the observation that Notch1 gain of function confers a selective advantage to SCL-LMO1 transgenic thymocytes. Accordingly, a hyperactive Notch1 allele accelerates leukemia onset induced by SCL-LMO1 and bypasses the requirement for pre-TCR signaling. Finally, the time to leukemia induced by the three transgenes corresponds to the time required for clonal expansion from a single leukemic stem cell, suggesting that SCL, LMO1, and Notch1 gain of function, together with an active pre-TCR, might represent the minimum set of complementing events for the transformation of susceptible thymocytes.

Terence H. Rabbitts - One of the best experts on this subject based on the ideXlab platform.

  • an antibody inhibitor of the lmo2 protein complex blocks its normal and tumorigenic functions
    Oncogene, 2008
    Co-Authors: M. Natividad Lobato, Alex Appert, Tomoyuki Tanaka, Lesley F. Drynan, Terence H. Rabbitts
    Abstract:

    The LIM-domain protein LMO2 is a T-cell oncogenic protein first recognized by gene activation through chromosomal translocations, but it is also responsible for leukaemias arising as secondary, adverse effects in an X-SCID gene therapy trial. There are no specific reagents currently available to analyse the LMO2 multiprotein complex or to combat LMO2-dependent leukaemias. Accordingly, we have isolated an anti-LMO2 single chain Fv antibody fragment to determine if intracellular interference with LMO2-protein complexes can avert LMO2-dependent functions in normal and cancer settings. The anti-LMO2 single chain Fv, obtained using Intracellular Antibody Capture (IAC) technology, is specific for LMO2 among the LIM-only protein family and binds LMO2 through the third and fourth LIM fingers. Using vector-mediated expression of anti-LMO2 scFv, we show inhibition of Lmo2-dependent erythropoiesis but not endothelial development. We also demonstrate inhibition of Lmo2-dependent leukaemia in a mouse T-cell tumourigenesis transplantation assay with retroviral-mediated expression of anti-LMO2 scFv. Our studies establish that interference with the LMO2 multiprotein complex inhibits both normal and tumourigenic roles. The antibody fragment is a tool for dissecting LMO2 function in haematopoiesis and leukaemia and is a lead for development of therapeutics against LMO2-dependent T-ALL.

  • The LMO1 and LDB1 proteins interact in human T cell acute leukaemia with the chromosomal translocation t(11;14)(p15;q11).
    Oncogene, 1998
    Co-Authors: V. Valge-archer, Alan Forster, Terence H. Rabbitts
    Abstract:

    The ectopic expression of LMO1 or LMO2 in T cell acute leukaemias resulting from chromosomal translocations t(11;14)(p15;q11) or t(11;14)(p13;q11) respectively in a causal factor in tumorigenesis. LMO1 has been found as a heterodimer with a 46 Kd protein in a T cell line derived from a childhood T-acute leukaemia. This 46 Kd protein is the LIM-binding protein LDB1/NLI. The latter is a phosphoprotein and binds to LMO1 in its phosphorylated state and essentially all the LMO1 and LDB1 protein in the T cell line is part of the complex. Therefore, the LMO1-LDB1 interaction is likely to be involved in tumorigenesis after LMO1 is ectopically expressed following chromosomal translocation in T cells prior to development of acute leukaemias.

  • identification of the lmo4 gene encoding an interaction partner of the lim binding protein ldb1 nli1 a candidate for displacement by lmo proteins in t cell acute leukaemia
    Oncogene, 1998
    Co-Authors: Gerald Grütz, Alan Forster, Terence H. Rabbitts
    Abstract:

    The T cell oncogenes LMO1 and LMO2 are activated by distinct chromosomal translocations in childhood T cell acute leukaemias. Transgenic mouse models of this disease demonstrate that enforced expression of LMO1 and Lmo2 cause T cell leukaemias with long latency and that Lmo2 expression leads to an inhibition of the T cell differentiation programme, prior to overt disease. These functions appear to be partly mediated by interaction of LMO1 or LMO2 with the LIM-binding protein LDB1/NLI1. We have now identified a new member of the Lmo family, designated Lmo4, via its interaction with Ldb1. Lmo4 is widely expressed in mouse tissues, including adult thymus (mainly CD4, CD8-double positive T cells) and embryonic thymus (mainly CD4, CD8-double negative T cells). These characteristics imply that Ldb1-Lmo4 interaction may function in the T cell developmental programme and that enforced expression of LMO1 or LMO2 by chromosomal translocations or transgenesis may displace Lmo4 from this complex and thereby influence T cell differentiation prior to T cell tumour occurrence.

  • Identification of the LMO4 gene encoding an interaction partner of the LIM-binding protein LDB1/NLI1: a candidate for displacement by LMO proteins in T cell acute leukaemia
    Oncogene, 1998
    Co-Authors: Gerald Grütz, Alan Forster, Terence H. Rabbitts
    Abstract:

    The T cell oncogenes LMO1 and LMO2 are activated by distinct chromosomal translocations in childhood T cell acute leukaemias. Transgenic mouse models of this disease demonstrate that enforced expression of LMO1 and Lmo2 cause T cell leukaemias with long latency and that Lmo2 expression leads to an inhibition of the T cell differentiation programme, prior to overt disease. These functions appear to be partly mediated by interaction of LMO1 or LMO2 with the LIM-binding protein LDB1/NLI1. We have now identified a new member of the Lmo family, designated Lmo4, via its interaction with Ldb1. Lmo4 is widely expressed in mouse tissues, including adult thymus (mainly CD4, CD8-double positive T cells) and embryonic thymus (mainly CD4, CD8-double negative T cells). These characteristics imply that Ldb1-Lmo4 interaction may function in the T cell developmental programme and that enforced expression of LMO1 or LMO2 by chromosomal translocations or transgenesis may displace Lmo4 from this complex and thereby influence T cell differentiation prior to T cell tumour occurrence.

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