Yanzhu Yang

Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/−- and c-kit-Dependent Bone Marrow

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.

Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg-/- mice in vivo

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow failure and complex congenital anomalies. Although mutations in FA genes result in a characteristic phenotype in the hematopoietic stem/progenitor cells (HSPCs), little is known about the consequences of a nonfunctional FA pathway in other stem/progenitor cell compartments. Given the intense functional interactions between HSPCs and the mesenchymal microenvironment, we investigated the FA pathway on the cellular functions of murine mesenchymal stem/progenitor cells (MSPCs) and their interactions with HSPCs in vitro and in vivo. Here, we show that loss of the murine homologue of FANCG (Fancg) results in a defect in MSPC proliferation and in their ability to support the adhesion and engraftment of murine syngeneic HSPCs in vitro or in vivo. Transplantation of wild-type (WT) but not Fancg(-/-) MSPCs into the tibiae of Fancg(-/-) recipient mice enhances the HSPC engraftment kinetics, the BM cellularity, and the number of progenitors per tibia of WT HSPCs injected into lethally irradiated Fancg(-/-) recipients. Collectively, these data show that FA proteins are required in the BM microenvironment to maintain normal hematopoiesis and provide genetic and quantitative evidence that adoptive transfer of WT MSPCs enhances hematopoietic stem cell engraftment.

The tumor suppressor CDKN3 controls mitosis

A genome-wide screen of phosphatases that control mitosis identified CDKN3, which acts through the CDC2 signaling axis.

Fanconi anemia signaling network regulates the spindle assembly checkpoint

Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.

Neurofibromin-deficient Schwann cells have increased lysophosphatidic acid dependent survival and migration—implications for increased neurofibroma formation during pregnancy

Neurofibromas are the clinical hallmark of neurofibromatosis Type 1 (NF1), a genetic disorder caused by mutations of the NF1 tumor suppressor gene, which encodes neurofibromin that functions as a GTPase activating protein (GAP) for Ras. During pregnancy, up to 50% of existing neurofibromas enlarge and as many as 60% of new neurofibromas appear for the first time. Lysophosphatidic acid (LPA) is a prototypic lysophospholipid that modulates cell migration and survival of Schwann cells (SCs) and is made in increasing concentrations throughout pregnancy. We addressed the influence of LPA on the biochemical and cellular functions of SCs with a homozygous mutation of the murine homologue of the NF1 gene (Nf1−/−). LPA promoted F‐actin polymerization and increased migration and survival of Nf1−/− SCs as compared to wild type (WT) SCs. Furthermore, LPA induced a higher level of Ras‐GTP and Akt phosphorylation in Nf1−/− SCs as compared to WT cells. Pharmacologic inhibition or siRNA for the p85β regulatory subunit of Class I A PI3‐K significantly reduced LPA‐induced Schwann cell survival and migration. Introduction of NF1‐GRD reconstitution was sufficient to normalize the LPA‐mediated motility of Nf1−/− SCs. As LPA modulates excessive cell survival and motility of Nf1−/− SCs, which are the tumorigenic cells in NF1, targeting PI3‐K may be a potential therapeutic approach in diminishing the development and progression of neurofibromas in pregnant women with NF1.