A Moloney Murine Leukemia Virus-Based Retrovirus with 4070A Long Terminal Repeat Sequences Induces a High Incidence of Myeloid as Well as Lymphoid Neoplasms

Wolff, Linda; Koller, Richard; Hu, Xinrong; Anver, Miriam R.

doi:10.1128/jvi.77.8.4965-4971.2003

Cited by 50 publications

(51 citation statements)

References 32 publications

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“…20 The injection of MOL4070LTR profoundly accelerated the onset of the disease in the Fbxl10 Tg group (median survival 5 274 days, P , .0001) ( Figure 1D). We also applied a chemically (N-ethyl-N-nitrosourea [ENU]) induced leukemia model to the same cohort, which enhanced leukemogenesis in Tg mice (median survival 5 210 days, P , .0001) ( Figure 1E).…”

Section: Fbxl10 Transgenic Mice Spontaneously Develop Myeloid and B-lmentioning

confidence: 99%

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Ueda¹,

Nagamachi

Takubo

et al. 2015

Blood

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• Fbxl10 is a bona fide oncogene in vivo. • Fbxl10 overexpression inHSCs induces mitochondrial metabolic activation and enhanced expression of Nsg2.We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for 27/7q2 syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation. (Blood. 2015;125(22):3437-3446) IntroductionAppropriate patterns of epigenetic alterations in histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases such as cancer. 1 We previously generated knockout mice for Samd9L (which was cloned as a candidate gene for the 27/7q2 syndrome frequently that is observed in myelodysplastic syndrome and acute leukemia patients) and demonstrated that mice deficient in Samd9L developed leukemia after a long latent period. 2 In addition, retroviral insertional mutagenesis revealed that the onset of the disease was highly accelerated with upregulation of F-box and leucine-rich repeat protein 10 (Fbxl10) or ectopic virus integration 1 (Evi1). 2 Clinically, an elevated expression of Fbxl10 is observed in patients with acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL), seminoma, and pancreatic ductal adenocarcinoma. [3][4][5][6] These findings prompted us to further investigate the role of Fbxl10 in leukemia development in vivo.Fbxl10 belongs to the JmjC domain-containing histone demethylases, and contains an N-terminal JmjC domain, followed by a CXXC zinc finger domain, a plant homeodomain finger, an F-box, and 8 leucine-rich repeats. 7 Fbxl10 preferentially demethylates the dimethylation of histone H3 at lysine 36 (H3K36me2), but not H3K36me1 and H3K36me3. 6,8 Fbxl10 was also recently reported to mediate the monoubiquitination of t...

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Section: Fbxl10 Transgenic Mice Spontaneously Develop Myeloid and B-lmentioning

confidence: 99%

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Ueda¹,

Nagamachi

Takubo

et al. 2015

Blood

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“…19 Briefly, pups received a single intraperitoneal injection containing approximately 2 ϫ 10 6 viral particles between 3 and 5 days of age. Genomic DNA was extracted from the bone marrow and/or spleen of mice that developed AML, and the host-viral junction fragments were cloned and mapped as described.…”

Section: Insertional Mutagenesismentioning

confidence: 99%

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus

Haigis

McDaniel³

et al. 2011

Blood

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“…We used the MOL4070LTR retrovirus (33) to perform RIM in Mx1-Cre, Kras G12D mice. Here we show that aberrant Ikaros expression due to viral integrations is a frequent early event and that somatic Notch1 mutations arise later and cooperate with oncogenic Kras in leukemogenesis.…”

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confidence: 99%

Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Dail¹,

Li²,

McDaniel³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras G12D mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes Kras G12D expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to γ-secretase inhibition. In addition, Kras G12D T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras G12D , and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies.

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A Moloney Murine Leukemia Virus-Based Retrovirus with 4070A Long Terminal Repeat Sequences Induces a High Incidence of Myeloid as Well as Lymphoid Neoplasms

Cited by 50 publications

References 32 publications

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus

Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

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A Moloney Murine Leukemia Virus-Based Retrovirus with 4070A Long Terminal Repeat Sequences Induces a High Incidence of Myeloid as Well as Lymphoid Neoplasms

Cited by 50 publications

References 32 publications

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus

Mutant Ikzf1, Kras G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

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Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents