LETTER TO BLOOD| MARCH 26, 2020
Ruxolitinib can cause weight gain by blocking leptin signaling in the brain via JAK2/STAT3Nicole Mollé , Spencer Krichevsky , Pouneh Kermani , Richard T. Silver , Ellen Ritchie , Joseph M. Scandura
Blood (2020) 135 (13): 1062–1066.
https://doi.org/10.1182/blood.2019003050
Subjects:
Clinical Trials and Observations, Myeloid Neoplasia
Topics:
leptin, ruxolitinib, stat3 protein, weight gain, signal transduction, brain, obesity, myeloproliferative disease
TO THE EDITOR:
Acquired mutations leading to aberrant activation of JAK/STAT signaling are common in myeloproliferative neoplasms (MPNs).1 Ruxolitinib is a JAK1/2 tyrosine kinase inhibitor used to treat patients with certain MPNs.2-6 The US Food and Drug Administration originally approved ruxolitinib for the treatment of advanced myelofibrosis (MF) because of its efficacy reducing symptoms and splenomegaly in this morbid disease.4-6 Weight gain among cachectic patients treated with ruxolitinib was quickly identified and reported among measures of improved quality of life.4-8 Although the original rationale was to disrupt pathogenic signaling via the mutated JAK2(V617F), ruxolitinib proved efficacious in patients with or without this mutation. Ruxolitinib use has since become more widespread. Now with US Food and Drug Administration approval for polycythemia vera2 and graft-versus-host disease9,10 and with an ever-expanding pool of indications being sought,11,12...
REFERENCES1.Quintás-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res. 2013;19(8):1933-1940.
2.Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435.
3.Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis [published correction appears in Leukemia. 2017;31(3):775]. Leukemia. 2016;30(8):1701-1707.
4.Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
5.Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.
6.Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127.
7.Mesa RA, Verstovsek S, Gupta V, et al. Effects of ruxolitinib treatment on metabolic and nutritional parameters in patients with myelofibrosis from COMFORT-I. Clin Lymphoma Myeloma Leuk. 2015;15(4):214-221.
8.Mesa RA, Scherber RM, Geyer HL. Reducing symptom burden in patients with myeloproliferative neoplasms in the era of Janus kinase inhibitors. Leuk Lymphoma. 2015;56(7):1989-1999.
9.Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062-2068.
10.von Bubnoff N, Ihorst G, Grishina O, et al. Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628). BMC Cancer. 2018;18(1):1132.
11.Verstovsek S, Passamonti F, Rambaldi A, et al. Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results. Blood. 2017;130(15):1768-1771.
12.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897.
13.Mesa R, Verstovsek S, Gupta V, et al. Improvement in weight and total cholesterol and their association with survival in ruxolitinib-treated patients with myelofibrosis from COMFORT-I [abstract]. Blood. 2012;120(21). Abstract 1733.
14.de Luca C, Kowalski TJ, Zhang Y, et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest. 2005;115(12):3484-3493.
15.Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356(3):237-247.
16.Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269(5223):543-546.
17.Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432.
18.Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology. 1997;138(10):4489-4492.
19.Ellacott KL, Cone RD. The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Lond B Biol Sci. 2006;361(1471):1265-1274.
20.Dodd GT, Worth AA, Nunn N, et al. The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab. 2014;20(4):639-649.
21.Elias CF, Aschkenasi C, Lee C, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron. 1999;23(4):775-786.
22.Prieur X, Tung YC, Griffin JL, Farooqi IS, O』Rahilly S, Coll AP. Leptin regulates peripheral lipid metabolism primarily through central effects on food intake. Endocrinology. 2008;149(11):5432-5439.
23.Farooqi IS, Bullmore E, Keogh J, Gillard J, O』Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behavior. Science. 2007;317(5843):1355.
24.Münzberg H, Huo L, Nillni EA, Hollenberg AN, Bjørbaek C. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology. 2003;144(5):2121-2131.
25.Piper ML, Unger EK, Myers MG Jr., Xu AW. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol Endocrinol. 2008;22(3):751-759.
26.Haile WB, Gavegnano C, Tao S, Jiang Y, Schinazi RF, Tyor WR. The Janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model. Neurobiol Dis. 2016;92(Pt B):137-143.
27.Reeves PM, Abbaslou MA, Kools FRW, et al. Ruxolitinib sensitizes ovarian cancer to reduced dose Taxol, limits tumor growth and improves survival in immune competent mice [published correction in Oncotarget. 2018;9(54):30472]. Oncotarget. 2017;8(55):94040-94053.
28.Pan WW, Myers MG Jr. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci. 2018;19(2):95-105.
29.Sinha MK, Opentanova I, Ohannesian JP, et al. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest. 1996;98(6):1277-1282.
30.Caro JF, Kolaczynski JW, Nyce MR, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet. 1996;348(9021):159-161.
31.Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996;2(5):589-593.
32.Ahrén B, Larsson H, Wilhelmsson C, Näsman B, Olsson T. Regulation of circulating leptin in humans. Endocrine. 1997;7(1):1-8.
© 2020 by The American Society of Hematology
This program is developed by Focus Insight with the permission of American Society of Hematology, Inc. The content are excerpted from the journal Blood. Copyright © 2019 The American Society of Hematology. All rights reserved. 「American Society of Hematology」, 「ASH」 and the ASH Logo are registered trademarks of the American Society of Hematology.