Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses

Journal of Experimental Medicine

Volumn 213, Issue 3, 2016, Pages 415-431

  Lau, Colleen M ^a,b   Nish, Simone A ^b   Yogev, Nir ^c   Waisman, Ari ^c   Reiner, Steven L ^b   Reizis, Boris ^a,b  

^a NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^b NewYork Presbyterian Hospital   (United States)

^c JOHANNES GUTENBERG UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

FLT3 LIGAND; FLT3 LIGAND PROTEIN; MEMBRANE PROTEIN;

ADULT; ALLELE; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CD8+ T LYMPHOCYTE; CELL EXPANSION; CELL LINEAGE; CELL MATURATION; CELL SURFACE; CLASSICAL DENDRITIC CELL; CONTROLLED STUDY; DENDRITIC CELL; DOWN REGULATION; FEMALE; GENE DUPLICATION; GENE MUTATION; HOMEOSTASIS; INTERNAL TANDEM DUPLICATION; LEUKEMIA; LYMPHOCYTE PROLIFERATION; MALE; MOUSE; NONHUMAN; PLASMACYTOID DENDRITIC CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE; YOUNG ADULT; ANIMAL; C57BL MOUSE; CELL PROLIFERATION; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; METABOLISM; MUTATION; SIGNAL TRANSDUCTION;

ANIMALS; CD8-POSITIVE T-LYMPHOCYTES; CELL LINEAGE; CELL PROLIFERATION; DENDRITIC CELLS; DOWN-REGULATION; GENE DUPLICATION; GENE EXPRESSION REGULATION, LEUKEMIC; HOMEOSTASIS; LEUKEMIA; MEMBRANE PROTEINS; MICE, INBRED C57BL; MUTATION; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84961231186     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20150642     Document Type: Article

References (69)

1. Adolfsson, J., O.J. Borge, D. Bryder, K. Theilgaard-Mönch, I. Astrand-Grundström, E. Sitnicka, Y. Sasaki, and S.E. Jacobsen. 2001. Upregulation of Flt3 expression within the bone marrow Lin-Sca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity. 15:659-669. http://dx.doi.org/10.1016/S1074-7613(01)00220-5
2. Anandasabapathy, N., R. Feder, S. Mollah, S.W. Tse, M.P. Longhi, S. Mehandru, I. Matos, C. Cheong, D. Ruane, L. Brane, et al. 2014. Classical Flt3Ldependent dendritic cells control immunity to protein vaccine. J. Exp. Med. 211:1875-1891. http://dx.doi.org/10.1084/jem.20131397
3. Bachanova, V., S. Cooley, T.E. Defor, M.R. Verneris, B. Zhang, D.H. McKenna, J. Curtsinger, A. Panoskaltsis-Mortari, D. Lewis, K. Hippen, et al. 2014. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 123:3855-3863. http://dx.doi.org/10.1182/blood-2013-10-532531
4. Bailey, E.J., A.S. Duffield, S.M. Greenblatt, P.D. Aplan, and D. Small. 2013. Effect of FLT3 ligand on survival and disease phenotype in murine models harboring a FLT3 internal tandem duplication mutation. Comp. Med. 63:218-226.
5. Bar-On, L., T. Birnberg, K.L. Lewis, B.T. Edelson, D. Bruder, K. Hildner, J. Buer, K.M. Murphy, B. Reizis, and S. Jung. 2010. CX3CR1+ CD8α+ dendritic cells are a steady-state population related to plasmacytoid dendritic cells. Proc. Natl. Acad. Sci. USA. 107:14745-14750. http://dx.doi.org/10.1073/pnas.1001562107
6. Bar-On, L., T. Birnberg, K.W. Kim, and S. Jung. 2011. Dendritic cell-restricted CD80/86 deficiency results in peripheral regulatory T-cell reduction but is not associated with lymphocyte hyperactivation. Eur. J. Immunol. 41:291-298. http://dx.doi.org/10.1002/eji.201041169
7. Blankenberg, D., G. Von Kuster, N. Coraor, G. Ananda, R. Lazarus, M. Mangan, A. Nekrutenko, and J. Taylor. 2010. Galaxy: a web-based genome analysis tool for experimentalists. Curr Protoc Mol Biol. Chapter 19:Unit 19 10 11-21.
8. Blazar, B.R., B.M. Carreno, A. Panoskaltsis-Mortari, L. Carter, Y. Iwai, H. Yagita, H. Nishimura, and P.A. Taylor. 2003. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism. J. Immunol. 171:1272-1277. http://dx.doi.org/10.4049/jimmunol.171.3.1272
9. Brasel, K., H.J. McKenna, P.J. Morrissey, K. Charrier, A.E. Morris, C.C. Lee, D.E. Williams, and S.D. Lyman. 1996. Hematologic effects of flt3 ligand in vivo in mice. Blood. 88:2004-2012.
10. Breton, G., J. Lee, Y.J. Zhou, J.J. Schreiber, T. Keler, S. Puhr, N. Anandasabapathy, S. Schlesinger, M. Caskey, K. Liu, and M.C. Nussenzweig. 2015. Circulating precursors of human CD1c+ and CD141+ dendritic cells. J. Exp. Med. 212:401-413. http://dx.doi.org/10.1084/jem.20141441
11. Cancer Genome Atlas Research Network. 2013. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368:2059-2074. http://dx.doi.org/10.1056/NEJMoa1301689
12. Chilton, P.M., F. Rezzoug, I. Fugier-Vivier, L.A. Weeter, H. Xu, Y. Huang, M.B. Ray, and S.T. Ildstad. 2004. Flt3-ligand treatment prevents diabetes in NOD mice. Diabetes. 53:1995-2002. http://dx.doi.org/10.2337/diabetes.53.8.1995
13. Chu, S.H., D. Heiser, L. Li, I. Kaplan, M. Collector, D. Huso, S.J. Sharkis, C. Civin, and D. Small. 2012. FLT3-ITD knockin impairs hematopoietic stem cell quiescence/homeostasis, leading to myeloproliferative neoplasm. Cell Stem Cell. 11:346-358. http://dx.doi.org/10.1016/j.stem.2012.05.027
14. Collins, C.B., C.M. Aherne, E.N. McNamee, M.D. Lebsack, H. Eltzschig, P. Jedlicka, and J. Rivera-Nieves. 2012. Flt3 ligand expands CD103+ dendritic cells and FoxP3+ T regulatory cells, and attenuates Crohn'slike murine ileitis. Gut. 61:1154-1162. http://dx.doi.org/10.1136/gutjnl-2011-300820
15. Darrasse-Jèze, G., S. Deroubaix, H. Mouquet, G.D. Victora, T. Eisenreich, K.H. Yao, R.F. Masilamani, M.L. Dustin, A. Rudensky, K. Liu, and M.C. Nussenzweig. 2009. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206:1853-1862. http://dx.doi.org/10.1084/jem.20090746
16. Ding, L., T.J. Ley, D.E. Larson, C.A. Miller, D.C. Koboldt, J.S. Welch, J.K. Ritchey, M.A. Young, T. Lamprecht, M.D. McLellan, et al. 2012. Clonal evolution in relapsed acute myeloid leukaemia revealed by wholegenome sequencing. Nature. 481:506-510. http://dx.doi.org/10.1038/nature10738
17. Edelson, B.T., T.R. Bradstreet, K. Hildner, J.A. Carrero, K.E. Frederick, W. Kc, R. Belizaire, T. Aoshi, R.D. Schreiber, M.J. Miller, et al.. 2011. CD8α+ dendritic cells are an obligate cellular entry point for productive infection by Listeria monocytogenes. Immunity. 35:236-248. http://dx.doi.org/10.1016/j.immuni.2011.06.012
18. Fontenot, J.D., J.P. Rasmussen, L.M. Williams, J.L. Dooley, A.G. Farr, and A.Y. Rudensky. 2005. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 22:329-341. http://dx.doi.org/10.1016/j.immuni.2005.01.016
19. Geissmann, F., M.G. Manz, S. Jung, M.H. Sieweke, M. Merad, and K. Ley. 2010. Development of monocytes, macrophages, and dendritic cells. Science. 327:656-661. http://dx.doi.org/10.1126/science.1178331
20. Giardine, B., C. Riemer, R.C. Hardison, R. Burhans, L. Elnitski, P. Shah, Y. Zhang, D. Blankenberg, I. Albert, J. Taylor, et al. 2005. Galaxy: a platform for interactive large-scale genome analysis. Genome Res. 15:1451-1455. http://dx.doi.org/10.1101/gr.4086505
21. Ginhoux, F., K. Liu, J. Helft, M. Bogunovic, M. Greter, D. Hashimoto, J. Price, N. Yin, J. Bromberg, S.A. Lira, et al.. 2009. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206:3115-3130. http://dx.doi.org/10.1084/jem.20091756
22. Govindaraj, C., P. Tan, P. Walker, A. Wei, A. Spencer, and M. Plebanski. 2014. Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients. Clin. Cancer Res. 20:724-735. http://dx.doi.org/10.1158/1078-0432.CCR-13-1576
23. Hildner, K., B.T. Edelson, W.E. Purtha, M. Diamond, H. Matsushita, M. Kohyama, B. Calderon, B.U. Schraml, E.R. Unanue, M.S. Diamond, et al.. 2008. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science. 322:1097-1100. http://dx.doi.org/10.1126/science.1164206
24. Jan, M., T.M. Snyder, M.R. Corces-Zimmerman, P. Vyas, I.L. Weissman, S.R. Quake, and R. Majeti. 2012. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 4:149ra118. http://dx.doi.org/10.1126/scitranslmed.3004315
25. Jung, S., J. Aliberti, P. Graemmel, M.J. Sunshine, G.W. Kreutzberg, A. Sher, and D.R. Littman. 2000. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20:4106-4114. http://dx.doi.org/10.1128/MCB.20.11.4106-4114.2000
26. Karsunky, H., M. Merad, A. Cozzio, I.L. Weissman, and M.G. Manz. 2003. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J. Exp. Med. 198:305-313. http://dx.doi.org/10.1084/jem.20030323
27. Kharazi, S., A.J. Mead, A. Mansour, A. Hultquist, C. Böiers, S. Luc, N. Buza-Vidas, Z. Ma, H. Ferry, D. Atkinson, et al. 2011. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood. 118:3613-3621. http://dx.doi.org/10.1182/blood-2010-06-289207
28. Kim, J.M., J.P. Rasmussen, and A.Y. Rudensky. 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191-197. http://dx.doi.org/10.1038/ni1428
29. Kindler, T., D.B. Lipka, and T. Fischer. 2010. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 116:5089-5102. http://dx.doi.org/10.1182/blood-2010-04-261867
30. Klein, O., L.M. Ebert, D. Zanker, K. Woods, B.S. Tan, J. Fucikova, A. Behren, I.D. Davis, E. Maraskovsky, W. Chen, and J. Cebon. 2013. Flt3 ligand expands CD4+ FoxP3+ regulatory T cells in human subjects. Eur. J. Immunol. 43:533-539. http://dx.doi.org/10.1002/eji.201242603
31. Langmead, B., and S.L. Salzberg. 2012. Fast gapped-read alignment with Bowtie 2. Nat. Methods. 9:357-359. http://dx.doi.org/10.1038/nmeth.1923
32. Laouar, Y., T. Welte, X.Y. Fu, and R.A. Flavell. 2003. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity. 19:903-912. http://dx.doi.org/10.1016/S1074-7613(03)00332-7
33. Lee, B.H., Z. Tothova, R.L. Levine, K. Anderson, N. Buza-Vidas, D.E. Cullen, E.P. McDowell, J. Adelsperger, S. Fröhling, B.J.P. Huntly, et al. 2007. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 12:367-380. http://dx.doi.org/10.1016/j.ccr.2007.08.031
34. Lewis, K.L., and B. Reizis. 2012. Dendritic cells: arbiters of immunity and immunological tolerance. Cold Spring Harb. Perspect. Biol. 4:a007401. http://dx.doi.org/10.1101/cshperspect.a007401
35. Lewis, K.L., M.L. Caton, M. Bogunovic, M. Greter, L.T. Grajkowska, D. Ng, A. Klinakis, I.F. Charo, S. Jung, J.L. Gommerman, et al. 2011. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity. 35:780-791. http://dx.doi.org/10.1016/j.immuni.2011.08.013
36. 2AR agonist attenuate acute kidney injury. J. Clin. Invest. 122:3931-3942. http://dx.doi.org/10.1172/JCI63170
37. Liu, K., and M.C. Nussenzweig. 2010. Origin and development of dendritic cells. Immunol. Rev. 234:45-54. http://dx.doi.org/10.1111/j.0105-2896.2009.00879.x
38. Liu, K., C. Waskow, X. Liu, K. Yao, J. Hoh, and M. Nussenzweig. 2007. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat. Immunol. 8:578-583. http://dx.doi.org/10.1038/ni1462
39. Love, M.I., W. Huber, and S. Anders. 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:550. http://dx.doi.org/10.1186/s13059-014-0550-8
40. Maldonado, R.A., and U.H. von Andrian. 2010. How tolerogenic dendritic cells induce regulatory T cells. Adv. Immunol. 108:111-165. http://dx.doi.org/10.1016/B978-0-12-380995-7.00004-5
41. Maraskovsky, E., K. Brasel, M. Teepe, E.R. Roux, S.D. Lyman, K. Shortman, and H.J. McKenna. 1996. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med. 184:1953-1962. http://dx.doi.org/10.1084/jem.184.5.1953
42. Maraskovsky, E., E. Daro, E. Roux, M. Teepe, C.R. Maliszewski, J. Hoek, D. Caron, M.E. Lebsack, and H.J. McKenna. 2000. In vivo generation of human dendritic cell subsets by Flt3 ligand. Blood. 96:878-884.
43. McKenna, H.J., K.L. Stocking, R.E. Miller, K. Brasel, T. De Smedt, E. Maraskovsky, C.R. Maliszewski, D.H. Lynch, J. Smith, B. Pulendran, et al. 2000. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood. 95:3489-3497.
44. Mead, A.J., S. Kharazi, D. Atkinson, I. Macaulay, C. Pecquet, S. Loughran, M. Lutteropp, P. Woll, O. Chowdhury, S. Luc, et al. 2013. FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors. Cell Reports. 3:1766-1776. http://dx.doi.org/10.1016/j.celrep.2013.04.031
45. Merad, M., P. Sathe, J. Helft, J. Miller, and A. Mortha. 2013. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31:563-604. http://dx.doi.org/10.1146/annurev-immunol-020711-074950
46. O'Keeffe, M., H. Hochrein, D. Vremec, J. Pooley, R. Evans, S. Woulfe, and K. Shortman. 2002. Effects of administration of progenipoietin 1, Flt-3 ligand, granulocyte colony-stimulating factor, and pegylated granulocytemacrophage colony-stimulating factor on dendritic cell subsets in mice. Blood. 99:2122-2130. http://dx.doi.org/10.1182/blood.V99.6.2122
47. Parcells, B.W., A.K. Ikeda, T. Simms-Waldrip, T.B. Moore, and K.M. Sakamoto. 2006. FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. Stem Cells. 24:1174-1184. http://dx.doi.org/10.1634/stemcells.2005-0519
48. Rickmann, M., J. Krauter, K. Stamer, M. Heuser, G. Salguero, E. Mischak-Weissinger, A. Ganser, and R. Stripecke. 2011. Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication. Ann. Hematol. 90:1047-1058. http://dx.doi.org/10.1007/s00277-011-1231-2
49. Rickmann, M., L. Macke, B.S. Sundarasetty, K. Stamer, C. Figueiredo, R. Blasczyk, M. Heuser, J. Krauter, A. Ganser, and R. Stripecke. 2013. Monitoring dendritic cell and cytokine biomarkers during remission prior to relapse in patients with FLT3-ITD acute myeloid leukemia. Ann. Hematol. 92:1079-1090. http://dx.doi.org/10.1007/s00277-013-1744-y
50. Rullé, S., M.D. Ah Kioon, C. Asensio, J. Mussard, H.K. Ea, M.C. Boissier, F. Lioté, and G. Falgarone. 2012. Adrenomedullin, a neuropeptide with immunoregulatory properties induces semi-mature tolerogenic dendritic cells. Immunology. 136:252-264. http://dx.doi.org/10.1111/j.1365-2567.2012.03577.x
51. Sathaliyawala, T., W.E. O'Gorman, M. Greter, M. Bogunovic, V. Konjufca, Z.E. Hou, G.P. Nolan, M.J. Miller, M. Merad, and B. Reizis. 2010. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity. 33:597-606. http://dx.doi.org/10.1016/j.immuni.2010.09.012
52. Schick, J., V. Vogt, M. Zerwes, T. Kroell, D. Kraemer, C.H. Köhne, A. Hausmann, R. Buhmann, J. Tischer, and H. Schmetzer. 2013. Antileukemic T-cell responses can be predicted by the composition of specific regulatory T-cell subpopulations. J. Immunother. 36:223-237. http://dx.doi.org/10.1097/CJI.0b013e31829180e7
53. Sela, U., P. Olds, A. Park, S.J. Schlesinger, and R.M. Steinman. 2011. Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice. J. Exp. Med. 208:2489-2496. http://dx.doi.org/10.1084/jem.20110466
54. Sen, B., S. Peng, D.M. Woods, I. Wistuba, D. Bell, A.K. El-Naggar, S.Y. Lai, and F.M. Johnson. 2012. STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma. Clin. Cancer Res. 18:127-139. http://dx.doi.org/10.1158/1078-0432.CCR-11-1889
55. Shlush, L.I., S. Zandi, A. Mitchell, W.C. Chen, J.M. Brandwein, V. Gupta, J.A. Kennedy, A.D. Schimmer, A.C. Schuh, K.W. Yee, et al. HALT Pan-Leukemia Gene Panel Consortium. 2014. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 506:328-333. http://dx.doi.org/10.1038/nature13038
56. Sitnicka, E., N. Buza-Vidas, S. Larsson, J.M. Nygren, K. Liuba, and S.E. Jacobsen. 2003. Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells. Blood. 102:881-886. http://dx.doi.org/10.1182/blood-2002-06-1694
57. Small, D. 2006. FLT3 mutations: biology and treatment. Hematology (Am Soc Hematol Educ Program). 2006:178-184. http://dx.doi.org/10.1182/asheducation-2006.1.178
58. Smith, C.C., Q. Wang, C.S. Chin, S. Salerno, L.E. Damon, M.J. Levis, A.E. Perl, K.J. Travers, S. Wang, J.P. Hunt, et al. 2012. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 485:260-263. http://dx.doi.org/10.1038/nature11016
59. Steinman, R.M., D. Hawiger, and M.C. Nussenzweig. 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21:685-711. http://dx.doi.org/10.1146/annurev.immunol.21.120601.141040
60. Svensson, M.N., S.E. Andersson, M.C. Erlandsson, I.M. Jonsson, A.K. Ekwall, K.M. Andersson, A. Nilsson, L. Bian, M. Brisslert, and M.I. Bokarewa. 2013. Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune arthritis. PLoS One. 8:e54884. http://dx.doi.org/10.1371/journal.pone.0054884
61. Swee, L.K., N. Bosco, B. Malissen, R. Ceredig, and A. Rolink. 2009. Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment. Blood. 113:6277-6287. http://dx.doi.org/10.1182/blood-2008-06-161026
62. Swords, R., C. Freeman, and F. Giles. 2012. Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. Leukemia. 26:2176-2185. http://dx.doi.org/10.1038/leu.2012.114
63. Takada, K., and S.C. Jameson. 2009. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9:823-832. http://dx.doi.org/10.1038/nri2657
64. Varol, C., A. Vallon-Eberhard, E. Elinav, T. Aychek, Y. Shapira, H. Luche, H.J. Fehling, W.D. Hardt, G. Shakhar, and S. Jung. 2009. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity. 31:502-512. http://dx.doi.org/10.1016/j.immuni.2009.06.025
65. Waskow, C., K. Liu, G. Darrasse-Jèze, P. Guermonprez, F. Ginhoux, M. Merad, T. Shengelia, K. Yao, and M. Nussenzweig. 2008. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat. Immunol. 9:676-683. http://dx.doi.org/10.1038/ni.1615
66. Yang, W., and Y. Xu. 2013. Clinical significance of Treg cell frequency in acute myeloid leukemia. Int. J. Hematol. 98:558-562. http://dx.doi.org/10.1007/s12185-013-1436-3
67. Zaiss, D.M., W.C. Gause, L.C. Osborne, and D. Artis. 2015. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity. 42:216-226. http://dx.doi.org/10.1016/j.immuni.2015.01.020
68. Zelenay, S., A.G. van der Veen, J.P. Böttcher, K.J. Snelgrove, N. Rogers, S.E. Acton, P. Chakravarty, M.R. Girotti, R. Marais, S.A. Quezada, et al.. 2015. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell. 162:1257-1270. http://dx.doi.org/10.1016/j.cell.2015.08.015
69. Zheng, R., E. Bailey, B. Nguyen, X. Yang, O. Piloto, M. Levis, and D. Small. 2011. Further activation of FLT3 mutants by FLT3 ligand. Oncogene. 30:4004-4014. http://dx.doi.org/10.1038/onc.2011.110