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

Abstract

• 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...

Recent advances in SCF ubiquitin ligase complex: Clinical implications

“…In support of the oncogenic role of FBXL10, transgenic mice that overexpression FBXL10 in hematopoietic stem cells (HSCs) developed myeloid or B-lymphoid leukemia with complete penetrance [152]. FBXL10 transgenic mice displayed an upregulation of Nsg2 (neuron-specific gene family member 2).…”

“…FBXL10 transgenic mice displayed an upregulation of Nsg2 (neuron-specific gene family member 2). HSCs from FBXL10 transgenic mice exhibited enhanced mitochondrial oxidative phosphorylation genes [152]. This transgenic mouse study dissected FBXL10 as a bona fide oncogene via regulation of metabolic proliferation and Nsg2-mediated impaired differentiation [152].…”

“…HSCs from FBXL10 transgenic mice exhibited enhanced mitochondrial oxidative phosphorylation genes [152]. This transgenic mouse study dissected FBXL10 as a bona fide oncogene via regulation of metabolic proliferation and Nsg2-mediated impaired differentiation [152]. Along these lines, FBXL10 is overexpressed in human PADC (pancreatic ductal adenocarcinoma) and is associated with tumor grade and stage and metastases [153].…”

Lysine-specific histone demethylases in normal and malignant hematopoiesis

“…KDM2B is an integral component of a non-canonical PRC1 complex and cooperates with PRC2 to regulate senescence, differentiation, and oncogenesis (17, 28, 30-33). KDM2B is upregulated in and is required for the oncogenicity of human ALL cell lines, whereas its overexpression in Sca-1 + cells suffices to induce mixed lineage leukemias with complete penetrance in mice (17, 34). On the other hand, deletion KDM2B expanded myeloid progenitors and accelerated Kras-driven AML through subversion of lineage specification pathways (17).…”

FBXL10 contributes to the progression of nasopharyngeal carcinoma via involving in PI3K/mTOR pathway

“…The F-box and leucine-rich repeat protein 10 (FBXL10, also known as JHDM1B, KDM2B and Ndy-1) belongs to the JmjC domain-containing histone demethylases and is considered as a tumor accelerator [7]. Penzo et al demonstrated that FBXL10 expression might regulate cancer cell growth in a p53-dependent manner [8].…”