jordan-kohlmeyer@uiowa.edu
Mentor: Dawn Quelle, Ph.D.
Lab Room: 4-411A BSB
Lab Phone: 319-335-7662

Defining the role of RABL6A in Neurofibromatosis Type I

Neurofibromatosis type I (NF1) is an autosomal dominant nervous system disorder and inherited cancer syndrome that affects 1 in 3,500 people worldwide. Nearly all NF1 patients exhibit benign dermal neurofibromas (DNs) that are small but numerous, while one-third develop larger plexiform neurofibromas (PNs) that are also benign but associated with significant morbidity due to their size and location. A major problem is that these PNs can transform into deadly malignant peripheral nerve sheath tumors (MPNSTs) in ~10% of patients. The NF1 disease results from inactivation of the NF1 gene, which encodes a tumor suppressor protein (named neurofibromin) that normally inhibits Ras signaling. Therefore, loss of neurofibromin results in enhanced Ras activity, promoting unrestrained cellular proliferation and survival through stimulation of MEK/ERK, PI3K/Akt and mTOR pathways. Aberrantly high Ras activity also leads to inactivation of protective tumor suppressors, particularly the p16INK4a-Rb and ARF-p53 pathways, which enables conversion of benign NF1 tumors into malignant lesions.

My studies aim to define the role of RABL6A, a novel oncogenic GTPase, in NF1. Our group previously showed that RABL6A is functionally linked to Akt-mTOR, ARF-p53 and Rb signaling, supporting our hypothesis that it is a critical new activator of Ras pathways that promotes cell transformation in NF1 associated cancers, such as MPNSTs. We are initially testing if and how RABL6A influences Ras signaling in cells that express wild-type or mutant NF1, using both human and porcine model systems. As part of our work, we have generated a new large animal model of NF1 in pigs through collaboration with other researchers at UI (Jess Sieren, Dave Meyerholz, Ben Darbro, Munir Tanas, Karin Panzir and Rebecca Dodd), Exemplar Genetics (Chris Rogers), and Sanford Research Institute (Jill Weimer). Excitingly, NF1 mutant pigs recapitulate the spectrum of pathologies seen in human patients, and they are providing unique cells in which to study RABL6A. Our research aims to understand the underlying mechanisms that drive cellular transformation in NF1 patients in order to identify new targets and develop new therapies.

Kohlmeyer, JL; Gordon, DJ; Tanas, MR; Monga, V; Dodd, RD; and Quelle, DE. CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets. International Journal of Molecular Sciences, 2020 Apr 24, 21(8), 3018; https://doi.org/10.3390/ijms21083018.

Kohlmeyer, JL; Kaemmer, CA; Pulliam, C; Maharjan, CK; Moreno Samayoa, A; Major, HJ; Cornick, KE; Knepper-Adrian, V; Khanna, R; Sieren, JC; Leidinger, M; Meyerholz, DK; Zamba, KD; Weimer, J; Dodd, RD; Darbro, B; Tanas, MR; and Quelle, DE. RABL6A is an essential driver of MPNSTs that negatively regulates the RB1 pathway and sensitizes tumor cells to CDK4/6 inhibitors. Clinical Cancer Research, 2020 Feb 21. doi: 10.1158/1078-0432.CCR-19-2706. [Epub ahead of print], PMID: 32086342.

White K, Swier V, Cain JT , Kohlmeyer J, Meyerholz DK, Tanas M, Uthoff j, Hammond E, Li H, Rohret FA, Goeken A, Change CH, Leidinger MR, Umesalma S, Wallace MR, Dodd RD, Panzer K, Tang AH, Darbro BW, Moutal A, Cai S, Li W, Bellampalli SS, Khanna R, Rogers CS, Sieren JC, Quelle DE, and Weimer JM. A porcine model of Neurofibromatosis Type I (NF1) that mimics the human disease. 2018. JCI Insight. Jun 21;3(12), pii: 120402. doi: 10.1172/jci.insight.120402. [Epub ahead of print], PMID: 29925695.

Umesalma, S., Kaemmer, C.A., Kohlmeyer, J.L., Letney, B., Schab, A.M., Reilly, J.A., Sheehy, R.M., Hagen, J., Tiwari, N., Zhan, F., Leidinger, M.R., O’Dorisio, T.M., Dillon, J., Merrill, R.A., Meyerholz, D.K., Perl, A.L., Brown, B.J., Braun, T.A., Scott, A.T., Ginader, T., Taghiyev, A.F., Zamba, G.K., Howe, J.R., Strack, S., Bellizzi, A.M., Narla, G., Darbro, B.W., Quelle, F.W., and Quelle, D.E.: RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth. Journal of Clinical Investigation, 2019. Feb 5. pii: 123049. doi: 10.1172/JCI123049. [Epub ahead of print] PMID: 30721156