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

Abstract

Wepreviously reported that deficiency forSamd9L, whichwascloned as a candidate gene for-7/7q-syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fb×l10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fb×l10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fb×l10 in hematopoietic stem cells (HSCs). Interestingly, Fb×l10 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. Fb×l10TgHSCsdisplayed enhancedexpression of neuron-specific gene familymember2 (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 Fb×l10 Tg HSCs, coupled with increased cellular adenosine 59-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fb×l10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fb×l10 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).