Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, ΔTrkA

Meyer, Johann; Rhein, Mathias; Schiedlmeier, Bernhard; Kustikova, Olga; Rudolph, Cornelia; Kamino, Kenji; Neumann, Thomas; Yang, Min; Wahlers, Anke; Reuther, Gary W.; Schlegelberger, Brigitte; Ganser, Arnold; Baum, Christopher; Li, Z

doi:10.1038/sj.leu.2404882

Cited by 33 publications

(42 citation statements)

References 46 publications

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“…To study whether naïve T cells are also resistant to transformation, HSCs/HPCs from three C57BL/6 Ly5.1 mice were transduced with the gammaretroviral vector SF91-DTrkA expressing an oncogenic, constitutively active form of TrkA 8 or with MP91-eGFP as a control vector (Supplementary Figure S1) and then transplanted into five sublethally irradiated Rag-1 À / À Ly5.2 mice (Figure 1a). In our previous study, 7 DTrkA was the most potent oncogene, with which we had shown resistance of memory T cells to development of MTCLs.…”

Section: Resultsmentioning

confidence: 99%

T-cell receptor diversity prevents T-cell lymphoma development

et al. 2012

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Mature T-cell lymphomas (MTCLs) have an extremely poor prognosis and are much less frequent than immature T-cell leukemias. This suggests that malignant outgrowth of mature T lymphocytes is well controlled. Indeed, in a previous study we found that mature T cells are resistant to transformation with known T-cell oncogenes. Here, however, we observed that T-cell receptor (TCR) mono-/oligoclonal mature T cells from TCR transgenic (tg) mice (OT-I, P14) expressing the oncogenes NPM/ALK or DTrkA readily developed MTCLs in T-cell-deficient recipients. Analysis of cell surface markers largely ruled out that TCR tg lymphomas were derived from T-cell precursors. Furthermore, cotransplanted non-modified TCR polyclonal T cells suppressed malignant outgrowth of oncogene expressing TCR tg T lymphocytes. A dominant role of an anti-leukemic immune response or Tregs in the control of MTCLs seems unlikely as naïve T cells derived from oncogene expressing stem cells, which should be tolerant to leukemic antigens, as well as purified CD4 and CD8 were resistant to transformation. However, our results are in line with a model in which homeostatic mechanisms that stabilize the diversity of the normal T-cell repertoire, for example, clonal competition, also control the outgrowth of potentially malignant T-cell clones. This study introduces a new innate mechanism of lymphoma control.

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Section: Resultsmentioning

confidence: 99%

T-cell receptor diversity prevents T-cell lymphoma development

et al. 2012

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“…In more than half of the mice (5 of 9) that received transplants of SF91-⌬TrkA high -transduced HSCs/HPCs, we observed a hyperacute myeloid proliferation, previously termed "transient leukemia" (TL), 10 with a latency of less than 12 days (Table 1). This TL was characterized by significant spleen enlargement (up to 4.8 g; Table S1C).…”

Section: Oncogenes Transform Primary Murine Hscs/hpcsmentioning

confidence: 95%

“…10 The vector is referred to as SF91-⌬TrkA. The vector MP91-wPRE was shown to support high transgene expression in mouse transplantation models.…”

Section: Retroviral Vectors/cloningmentioning

confidence: 99%

“…For ⌬TrkA, a high copy and a low copy batch of cells were prepared because pilot experiments showed that high copy numbers led to rapid death of the animals from a polyclonal myeloproliferative disease and ⌬TrkA had been reported to produce hematologic malignancies also in a single copy setting. 10 Transduced T cells and HSCs/HPCs were transplanted into RAG-1-deficient recipients. Six weeks after gene transfer, animals were analyzed for donor cell engraftment and transgene (eGFP) expression.…”

Section: Study Design and Retroviral Vectorsmentioning

confidence: 99%

“…⌬TrkA was found to generate acute myeloid leukemia as well as immature T-cell leukemia after retroviral gene transfer and a very short latency period. 10 Activation of potential oncogenes by retroviral insertion alone is not thought to be sufficient for transformation. 11,12 One factor that may determine the penetrance of overt leukemia after oncogene activation is thought to be the level of cell lineage differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Resistance of mature T cells to oncogene transformation

Newrzela

Cornils

et al. 2008

Blood

183

141

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Leukemia caused by retroviral insertional mutagenesis after stem cell gene transfer has been reported in several experimental animals and in patients treated for X-linked severe combined immunodeficiency. Here, we analyzed whether gene transfer into mature T cells bears the same genotoxic risk. To address this issue in an experimental "worst case scenario," we transduced mature T cells and hematopoietic progenitor cells from C57BL/6 (Ly5.1) donor mice with high copy numbers of gamma retroviral vectors encoding the potent T-cell oncogenes LMO2, TCL1, or ⌬TrkA, a constitutively active mutant of TrkA. After transplantation into RAG-1-deficient recipients (Ly5.2), animals that received stem cell transplants developed T-cell lymphoma/leukemia for all investigated oncogenes with a characteristic phenotype and after characteristic latency periods. Ligation-mediated polymerase chain reaction analysis revealed monoclonality or oligoclonality of the malignancies. In striking contrast, none of the mice that received IntroductionGamma retroviral vectors integrate into the target cell genome, thus supporting long-term transgene expression. They are among the best-established therapeutic vector systems and have successfully been used for gene transfer to hematopoietic stem cells (HSCs) in the treatment of X-linked and adenosine deaminase-deficient severe combined immunodeficiency (SCID). A limitation of retroviral gene transfer to HSC has been the risk of insertional mutagenesis, which was reported to lead to the preferential expansion of individual hematopoietic cell clones (clonal dominance) or even overt leukemia/lymphoma. 1 At the date of submission, 4 human cases of leukemia resulting from retroviral insertional mutagenesis had been described, all after initially successful treatment of X-linked SCID. 2-4 Three of these cases were associated with the activation of the T-cell oncogene LMO2 near the retroviral integration site, and all cases manifested as T-cell lineage leukemias. 5 It has been long known that leukemias can be linked to specific chromosomal translocations that juxtapose a strong promoter/ enhancer element to a cellular oncogene, such as LMO2 or TCL1, 6,7 thus up-regulating the expression of the oncogene. For several of these oncogenes, transgenic mouse models have confirmed their transforming activity. 8,9 LMO2-transgenic mice develop T-cell leukemia of an immature phenotype, whereas TCL1 is found to induce mature T-cell malignancies. A deletion mutant of the receptor tyrosine kinase TrkA (⌬TrkA) for nerve growth factor was described that is constitutively active. ⌬TrkA was found to generate acute myeloid leukemia as well as immature T-cell leukemia after retroviral gene transfer and a very short latency period. 10 Activation of potential oncogenes by retroviral insertion alone is not thought to be sufficient for transformation. 11,12 One factor that may determine the penetrance of overt leukemia after oncogene activation is thought to be the level of cell lineage differentiation. In general, stem cells a...

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Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models

et al. 2010

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Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an anticancer agent. However, only a fraction of cancer patients responds to the drug, and no biomarkers are available to predict tumor sensitivity. Recently, we and others have obtained evidence for potential involvement of tropomyosin-related kinase (TRK) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) in leukemia. In the present study, we tested the therapeutic effect of Rapamycin and its analog RAD001 on altered TRK-induced leukemia in a murine model. Daily treatment with Rapamycin (2 mg/kg) or RAD001 (1 mg/kg) significantly prolonged the survival of treated animals (n = 40) compared with the placebo group. Consistently, both mTOR and S6 proteins were strongly dephosphorylated in vitro and in vivo after treatment with Rapamycin or RAD001. However, Rapamycin did not completely inhibit mTORC1-dependent phosphorylation of 4E-BP1. With exception of one mouse showing slight reactivation of Akt after treatment, no reactivation of MAPK or Akt pathways was observed in other resistant tumors. Interestingly, leukemic cells isolated from a Rapamycin-resistant mouse were still highly sensitive to Rapamycin in vitro. Our findings suggest that altered TRK signaling may be a good predictor of tumor sensitivity to mTOR inhibition and that pathways other than MAPK and Akt exist that may trigger resistance of leukemic cells to Rapamycin in vivo.

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Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, ΔTrkA

Cited by 33 publications

References 46 publications

T-cell receptor diversity prevents T-cell lymphoma development

T-cell receptor diversity prevents T-cell lymphoma development

Resistance of mature T cells to oncogene transformation

Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models

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