Advertisement

Current Hematologic Malignancy Reports

, Volume 14, Issue 3, pp 145–153 | Cite as

Key Role of Inflammation in Myeloproliferative Neoplasms: Instigator of Disease Initiation, Progression. and Symptoms

  • Laura F. Mendez Luque
  • Amanda L. Blackmon
  • Gajalakshmi Ramanathan
  • Angela G. FleischmanEmail author
Myeloproliferative Neoplasms (B Stein, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Myeloproliferative Neoplasms

Abstract

Purpose of Review

Chronic inflammation is a characteristic feature of myeloproliferative neoplasm (MPN) and impacts many aspects of the disease including initiation, progression, and symptomatology.

Recent Findings

The chronic inflammatory state of MPN results from disruption of immune signaling pathways leading to overproduction of inflammatory cytokines by both the neoplastic clones and bystander immune cells. This chronic inflammation may allow for the neoplastic clone to gain a selective advantage. The symptomatic burden felt by MPN patients may be a result of the chronic inflammation associated with MPN, as several cytokines have been linked with different symptoms. Pharmacologic as well as nonpharmacologic treatments of the inflammatory component of this disease may lead to decreased symptomatic burden, prevention of disease progression, and improvement in overall disease trajectory.

Summary

Inflammation plays a key role in the pathogenesis of MPN and represents an important therapeutic target.

Keywords

Myeloproliferative neoplasm JAK/STAT signaling Inflammation in cancer Diet in cancer Lifestyle in cancer Inflammatory cytokines Fatigue Quality of life Nonpharmacological approaches 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Hoermann G, Greiner G, Valent P. Cytokine regulation of microenvironmental cells in myeloproliferative neoplasms. Mediat Inflamm. 2015;2015:869242.Google Scholar
  2. 2.
    Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1356–63.Google Scholar
  3. 3.
    Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010;115(25):5232–40.Google Scholar
  4. 4.
    Hasselbalch HC. Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res. 2013;37(2):214–20.  https://doi.org/10.1016/j.leukres.2012.10.020.
  5. 5.
    •• Fleischman AG, Aichberger KJ, Luty SB, Bumm TG, Petersen CL, Doratotaj S, et al. TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood. 2011;118(24):6392–8 This study demonstrates that JAK2 mutant hematopoietic progenitors are resistant to inflammation and that this may allow for the emergence of JAK2 mutant cells in the context of chronic inflammation. Google Scholar
  6. 6.
    •• Kleppe M, Kwak M, Koppikar P, Riester M, Keller M, Bastian L, et al. JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov. 2015;5(3):316–31 This study reveals that both mutant and non-mutant cells in MPN contribute to the inflammatory state in MPN. Google Scholar
  7. 7.
    •• Lai HY, Brooks SA, Craver BM, Morse SJ, Nguyen TK, Haghighi N, et al. Defective negative regulation of Toll-like receptor signaling leads to excessive TNF-alpha in myeloproliferative neoplasm. Blood Adv. 2019;3(2):122–31 This study shows that MPN monocytes have difficulty turning off inflammatory signals and this contributes to inflammation in MPN. Google Scholar
  8. 8.
    Kristinsson SY, Landgren O, Samuelsson J, Bjorkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95(7):1216–20.Google Scholar
  9. 9.
    Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–62.Google Scholar
  10. 10.
    •• Fisher DAC, Miner CA, Engle EK, Hu H, Collins TB, Zhou A, et al. Cytokine production in myelofibrosis exhibits differential responsiveness to JAKSTAT, MAP kinase, and NFκB signaling. Leukemia. 2019.  https://doi.org/10.1038/s41375-019-0379-y. This study demonstrates that JAK inhibition is not sufficient to return cytokines to normal in MPN.
  11. 11.
    Fisher DAC, Malkova O, Engle EK, Miner CA, Fulbright MC, Behbehani GK, et al. Mass cytometry analysis reveals hyperactive NF kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia. 2017;31(9):1962–74.Google Scholar
  12. 12.
    Yang Y, Nath D, Dutta A, Crooks PA, Mohi G. The NF-KB inhibitor DMAPT in combination with ruxolitinib displays efficacy in Jak2V617F knock-in mouse model of myeloproliferative neoplasms. American Society of Hematology Annual Meeting; December 1, 2018; San Diego; 2018.Google Scholar
  13. 13.
    •• Kleppe M, Koche R, Zou L, van Galen P, Hill CE, Dong L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(4):785–7 This paper highlights the importance of targeting inflammation in MPN. Google Scholar
  14. 14.
    Johansson P, Mesa R, Scherber R, Abelsson J, Samuelsson J, Birgegard G, et al. Association between quality of life and clinical parameters in patients with myeloproliferative neoplasms. Leuk Lymphoma. 2012;53(3):441–4.Google Scholar
  15. 15.
    Mesa RA, Niblack J, Wadleigh M, Verstovsek S, Camoriano J, Barnes S, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international internet-based survey of 1179 MPD patients. Cancer. 2007;109(1):68–76.Google Scholar
  16. 16.
    Mitra D, Kaye JA, Piecoro LT, Brown J, Reith K, Mughal TI, et al. Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review. Cancer Med. 2013;2(6):889–98.Google Scholar
  17. 17.
    Abelsson J, Andreasson B, Samuelsson J, Hultcrantz M, Ejerblad E, Johansson B, et al. Patients with polycythemia vera have worst impairment of quality of life among patients with newly diagnosed myeloproliferative neoplasms. Leuk Lymphoma. 2013;54(10):2226–30.Google Scholar
  18. 18.
    •• Scherber R, Dueck AC, Johansson P, Barbui T, Barosi G, Vannucchi AM, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118(2):401–8 This paper describes the validation of the MPN-SAF symptom assessment form. Google Scholar
  19. 19.
    Scherber RM, Kosiorek HE, Senyak Z, Dueck AC, Clark MM, Boxer MA, et al. Comprehensively understanding fatigue in patients with myeloproliferative neoplasms. Cancer. 2016;122(3):477–85.Google Scholar
  20. 20.
    Bower JE, Ganz PA, Desmond KA, Bernaards C, Rowland JH, Meyerowitz BE, et al. Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer. 2006;106(4):751–8.Google Scholar
  21. 21.
    Musselman DL, Miller AH, Porter MR, Manatunga A, Gao F, Penna S, et al. Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry. 2001;158(8):1252–7.Google Scholar
  22. 22.
    Scherber RM, Geyer HL, Mesa RA. Quality of life in MPN comes of age as a therapeutic target. Curr Hematol Malig Rep. 2014;9(4):324–30.Google Scholar
  23. 23.
    Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer. 2001;92(6 Suppl):1684–8.Google Scholar
  24. 24.
    Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW. Fatigue and gene expression in human leukocytes: increased NF-kappaB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain Behav Immun. 2011;25(1):147–50.Google Scholar
  25. 25.
    Barbui T. How to manage thrombosis in myeloproliferative neoplasms. Curr Opin Oncol. 2011;23(6):654–8.Google Scholar
  26. 26.
    •• Geyer HL, Dueck AC, Scherber RM, Mesa RA. Impact of inflammation on myeloproliferative neoplasm symptom development. Mediat Inflamm. 2015;2015:284706 This paper correlates specific cytokines with specific symptoms in MPN. Google Scholar
  27. 27.
    Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW. Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci. 2006;26(42):10709–16.Google Scholar
  28. 28.
    Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104(4):788–93.Google Scholar
  29. 29.
    Tisdale MJ. Cancer cachexia: metabolic alterations and clinical manifestations. Nutrition. 1997;13(1):1–7.Google Scholar
  30. 30.
    Bossola M, Muscaritoli M, Costelli P, Bellantone R, Pacelli F, Busquets S, et al. Increased muscle ubiquitin mRNA levels in gastric cancer patients. Am J Physiol Regul Integr Comp Physiol. 2001;280(5):R1518–23.Google Scholar
  31. 31.
    Ramos EJ, Suzuki S, Marks D, Inui A, Asakawa A, Meguid MM. Cancer anorexia-cachexia syndrome: cytokines and neuropeptides. Curr Opin Clin Nutr Metab Care. 2004;7(4):427–34.Google Scholar
  32. 32.
    Argiles JM, Busquets S, Lopez-Soriano FJ. The pivotal role of cytokines in muscle wasting during cancer. Int J Biochem Cell Biol. 2005;37(10):2036–46.Google Scholar
  33. 33.
    Pieri L, Bogani C, Guglielmelli P, Zingariello M, Rana RA, Bartalucci N, et al. The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera. Haematologica. 2009;94(11):1537–45.Google Scholar
  34. 34.
    Jin X, Zhao W, Kirabo A, Park SO, Ho WT, Sayeski PP, et al. Elevated levels of mast cells are involved in pruritus associated with polycythemia vera in JAK2V617F transgenic mice. J Immunol. 2014;193(2):477–84.Google Scholar
  35. 35.
    Jackson N, Burt D, Crocker J, Boughton B. Skin mast cells in polycythaemia vera: relationship to the pathogenesis and treatment of pruritus. Br J Dermatol. 1987;116(1):21–9.Google Scholar
  36. 36.
    Wang J, Ishii T, Zhang W, Sozer S, Dai Y, Mascarenhas J, et al. Involvement of mast cells by the malignant process in patients with Philadelphia chromosome negative myeloproliferative neoplasms. Leukemia. 2009;23(9):1577–86.Google Scholar
  37. 37.
    Boyle P. Cancer, cigarette smoking and premature death in Europe: a review including the Recommendations of European Cancer Experts Consensus Meeting, Helsinki, October 1996. Lung Cancer. 1997;17(1):1–60.Google Scholar
  38. 38.
    Fircanis S, Merriam P, Khan N, Castillo JJ. The relation between cigarette smoking and risk of acute myeloid leukemia: an updated meta-analysis of epidemiological studies. Am J Hematol. 2014;89(8):E125–32.Google Scholar
  39. 39.
    Kroll ME, Murphy F, Pirie K, Reeves GK, Green J, Beral V. Alcohol drinking, tobacco smoking and subtypes of haematological malignancy in the UK Million Women Study. Br J Cancer. 2012;107(5):879–87.Google Scholar
  40. 40.
    Leal AD, Thompson CA, Wang AH, Vierkant RA, Habermann TM, Ross JA, et al. Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in the Iowa Women’s Health Study cohort. Int J Cancer. 2014;134(7):1741–50.Google Scholar
  41. 41.
    Lindholm Sorensen A, Hasselbalch HC. Smoking and Philadelphia-negative chronic myeloproliferative neoplasms. Eur J Haematol. 2016;97(1):63–9.Google Scholar
  42. 42.
    Pedersen KM, Bak M, Sorensen AL, Zwisler AD, Ellervik C, Larsen MK, et al. Smoking is associated with increased risk of myeloproliferative neoplasms: a general population-based cohort study. Cancer Med. 2018;7(11):5796–802.Google Scholar
  43. 43.
    Jayasuriya NA EC, Hasselbalch HC, Sørensen A. Cigarette smoking, complete blood count, and myeloproliferative neoplasms – a meta-analysis. American Society of Hematology Annual Meeting. 2017;Abstract 3199.Google Scholar
  44. 44.
    Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol. 2013;160(1):70–9.Google Scholar
  45. 45.
    Weinberg I, Borohovitz A, Krichevsky S, Perlman R, Ben-Yehuda A, Ben-Yehuda D. Janus kinase V617F mutation in cigarette smokers. Am J Hematol. 2012;87(1):5–8.Google Scholar
  46. 46.
    Hasselbalch HC. Smoking as a contributing factor for development of polycythemia vera and related neoplasms. Leuk Res. 2015;39:1137–45.Google Scholar
  47. 47.
    Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731–6.Google Scholar
  48. 48.
    Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, Landman C, et al. Fungal microbiota dysbiosis in IBD. Gut. 2017;66(6):1039–48.Google Scholar
  49. 49.
    Staffas A, Burgos da Silva M, van den Brink MR. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood. 2017;129(8):927–33.Google Scholar
  50. 50.
    Balmer ML, Schurch CM, Saito Y, Geuking MB, Li H, Cuenca M, et al. Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J Immunol. 2014;193(10):5273–83.Google Scholar
  51. 51.
    •• Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129(6):729–39 This paper demonstrates the negative effects of chronic inflammation on hematopoietic stem cells. Google Scholar
  52. 52.
    Calcinotto A, Brevi A, Chesi M, Ferrarese R, Garcia Perez L, Grioni M, et al. Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression. Nat Commun. 2018;9(1):4832.Google Scholar
  53. 53.
    Keshteli AH, Millan B, Madsen KL. Pretreatment with antibiotics may enhance the efficacy of fecal microbiota transplantation in ulcerative colitis: a meta-analysis. Mucosal Immunol. 2017;10(2):565–6.Google Scholar
  54. 54.
    Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500(7464):585–8.Google Scholar
  55. 55.
    •• Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98 This paper describes clonal hematopoiesis of indeterminate potential and its association with adverse clinical outcomes. Google Scholar
  56. 56.
    •• Xie M, Lu C, Wang J, McLellan MD. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8 This paper demonstrates that clonal hematopoiesis is common among people with cancers. Google Scholar
  57. 57.
    Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Adv. 2018;2(22):3404–10.Google Scholar
  58. 58.
    Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 2017;130(6):742–52.Google Scholar
  59. 59.
    •• Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21(3):374–82.e4 This paper demonstrates clonal hematopoiesis is common in people with cancer. Google Scholar
  60. 60.
    Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A, et al. Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res. 1994;137(2 Suppl):S68–97.Google Scholar
  61. 61.
    Poluben L, Puligandla M, Neuberg D, Bryke CR, Hsu Y, Shumeiko O, et al. Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident. Am J Hematol. 2019;94(1):62–73.Google Scholar
  62. 62.
    Community health screening for JAK2(V617F) mutation Luzerne, Schuylkill and Carbon Counties, Pennsylvania In: Services USDoHaH, editor. Atlanta; 2011.Google Scholar
  63. 63.
    Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(6):761–70.Google Scholar
  64. 64.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.Google Scholar
  65. 65.
    Buffart LM, van Uffelen JG, Riphagen II, Brug J, van Mechelen W, Brown WJ, et al. Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2012;12:559.Google Scholar
  66. 66.
    Cote A, Daneault S. Effect of yoga on patients with cancer: our current understanding. Can Fam Physician. 2012;58(9):e475–9.Google Scholar
  67. 67.
    Harder H, Parlour L, Jenkins V. Randomised controlled trials of yoga interventions for women with breast cancer: a systematic literature review. Support Care Cancer. 2012;20(12):3055–64.Google Scholar
  68. 68.
    Sadja J, Mills PJ. Effects of yoga interventions on fatigue in cancer patients and survivors: a systematic review of randomized controlled trials. Explore. 2013;9(4):232–43.Google Scholar
  69. 69.
    Bower JE, Greendale G, Crosswell AD, Garet D, Sternlieb B, Ganz PA, et al. Yoga reduces inflammatory signaling in fatigued breast cancer survivors: a randomized controlled trial. Psychoneuroendocrinology. 2014;43:20–9.Google Scholar
  70. 70.
    Carson JW, Carson KM, Porter LS, Keefe FJ, Seewaldt VL. Yoga of awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer. 2009;17(10):1301–9.Google Scholar
  71. 71.
    Huberty J, Eckert R, Gowin K, Mitchell J, Dueck AC, Ginos BF, et al. Feasibility study of online yoga for symptom management in patients with myeloproliferative neoplasms. Haematologica. 2017;102(10):e384–e8.Google Scholar
  72. 72.
    Huberty J, Eckert R, Larkey L, Gowin K, Mitchell J, Mesa R. Perceptions of myeloproliferative neoplasm patients participating in an online yoga intervention: a qualitative study. Integr Cancer Ther. 2018;17(4):1150–62.Google Scholar
  73. 73.
    van Waart H, van Harten WH, Buffart LM, Sonke GS, Stuiver MM, Aaronson NK. Why do patients choose (not) to participate in an exercise trial during adjuvant chemotherapy for breast cancer? Psycho-oncology. 2016;25(8):964–70.Google Scholar
  74. 74.
    Smidowicz A, Regula J. Effect of nutritional status and dietary patterns on human serum C-reactive protein and interleukin-6 concentrations. Adv Nutr. 2015;6(6):738–47.Google Scholar
  75. 75.
    Turati F, Carioli G, Bravi F, Ferraroni M, Serraino D, Montella M, et al. Mediterranean Diet and Breast Cancer Risk. Nutrients. 2018;10(3):326.  https://doi.org/10.3390/nu10030326.
  76. 76.
    Castello A, Amiano P, Fernandez de Larrea N, Martin V, Alonso MH, Castano-Vinyals G, et al. Low adherence to the western and high adherence to the mediterranean dietary patterns could prevent colorectal cancer. Eur J Nutr. 2018.  https://doi.org/10.1007/s00394-018-1674-5.
  77. 77.
    Schulpen M, van den Brandt PA. Adherence to the Mediterranean diet and risk of lung cancer in the Netherlands Cohort Study. Br J Nutr. 2018;119(6):674–84.Google Scholar
  78. 78.
    Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study. J Am Coll Cardiol. 2004;44(1):152–8.Google Scholar
  79. 79.
    Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018;378(25):e34.Google Scholar
  80. 80.
    Scherber RM, Langlais BT, Geyer HL, Dueck AC, Kosiorek HE, Johnston C, et al editors. Nutrition and supplement use characteristics in the myeloproliferative neoplasms: results from the Nutrient Survey. American Society of Hematology Annual Meeting; Atlanta; 2017.Google Scholar
  81. 81.
    Scherber R GH, Dueck A, Johnston C, Langlais B, Padrnos L, Palmer J, Fleischman A, Mesa R. Nutritional needs and preferences of myeloproliferativen neoplasm patients: phase 1A of the Nutrient Study. 22nd Congress of the European Hematology Association Madrid; 2017. p. P377.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Laura F. Mendez Luque
    • 1
  • Amanda L. Blackmon
    • 2
  • Gajalakshmi Ramanathan
    • 2
  • Angela G. Fleischman
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Biological ChemistryUniversity of California IrvineIrvineUSA
  2. 2.Division of Hematology/Oncology, Department of MedicineUniversity of California IrvineIrvineUSA
  3. 3.Chao Family Comprehensive Cancer CenterUniversity of California IrvineIrvineUSA

Personalised recommendations