Review Article | Published:

Necroinflammation emerges as a key regulator of hematopoiesis in health and disease

Cell Death & Differentiation (2018) | Download Citation


The hematopoietic system represents an organ system with an exceptional capacity for the production of mature blood cells from a small and mostly quiescent pool of hematopoietic stem cells (HSCs). This extraordinary capacity includes self-renewal but also the propensity to rapidly respond to extrinsic needs, such as acute infections, severe inflammation, and wound healing. In recent years, it became clear that inflammatory signals such as cytokines, chemokine and danger signals from pathogens (PAMPs) or dying cells (DAMPs) impact on HSCs, shaping their proliferation status, lineage bias, and repopulating ability and subsequently increasing the output of mature effector cells. However, inflammatory danger signals negatively impact on the capacity of HSCs to self-renew and to maintain their stem cell capabilities. This is evidenced in conditions of chronic inflammation where bone marrow failure may originate from HSC exhaustion. Even in hematopoietic cancers, inflammatory signals shape the phenotype of the malignant clone as exemplified by necrosome-dependent inflammation elicited during malignant transformation in acute myeloid leukemia. Accordingly, understanding the contribution of inflammatory signals, and specifically necroinflammation, to HSC integrity, HSC long-term functionality, and malignant transformation has attracted substantial research and clinical interest. In this review, we highlight recent developments and open questions at the interplay between inflammation, regulated necrosis, and HSC biology in the context of blood cell development, acute and chronic inflammation, and hematopoietic cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and consequences of necroinflammation. Physiol Rev. 2018;98:727–80.

  2. 2.

    Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38:209–23.

  3. 3.

    Mulay SR, Linkermann A, Anders HJ. Necroinflammation in kidney disease. J Am Soc Nephrol. 2016;27:27–39.

  4. 4.

    Croker BA, Silke J, Gerlic M. Fight or flight: regulation of emergency hematopoiesis by pyroptosis and necroptosis. Curr Opin Hematol. 2015;22:293–301.

  5. 5.

    Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1:489–95.

  6. 6.

    Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A, Andrake M, et al. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc Natl Acad Sci USA. 2013;110:E3109–18.

  7. 7.

    He S, Liang Y, Shao F, Wang X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc Natl Acad Sci USA. 2011;108:20054–9.

  8. 8.

    Upton JW, Kaiser WJ, Mocarski ES. Virus inhibition of RIP3-dependent necrosis. Cell Host Microbe. 2010;7:302–13.

  9. 9.

    Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15:135–47.

  10. 10.

    Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.

  11. 11.

    Walczak H. Death receptor-ligand systems in cancer, cell death, and inflammation. Cold Spring Harb Perspect Biol. 2013;5:a008698.

  12. 12.

    Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 2017;24:1184–95.

  13. 13.

    Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2014;16:55–65.

  14. 14.

    Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell. 2013;153:1312–26.

  15. 15.

    de Almagro MC, Goncharov T, Newton K, Vucic D. Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. Cell Death Dis. 2015;6:e1800.

  16. 16.

    Najjar M, Saleh D, Zelic M, Nogusa S, Shah S, Tai A, et al. RIPK1 and RIPK3 kinases promote cell-death-independent inflammation by Toll-like receptor 4. Immunity. 2016;45:46–59.

  17. 17.

    Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135:1311–23.

  18. 18.

    Biton S, Ashkenazi. ANEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feed forward signaling. Cell. 2011;145:92–103.

  19. 19.

    Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman C, Zhu H, et al. A novel role for RIP1 kinase in mediating TNF alpha production. Cell Death Dis. 2012;3:e320.

  20. 20.

    Moriwaki K, Chan FK. Necrosis-dependent and independent signaling of the RIP kinases in inflammation. Cytokine Growth Factor Rev. 2014;25:167–74.

  21. 21.

    Yabal M, Muller N, Adler H, Knies N, Gross CJ, Damgaard RB, et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep. 2014;7:1796–808.

  22. 22.

    Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun. 2015;6:6282.

  23. 23.

    Moriwaki K, Bertin J, Gough PJ, Chan FK. A RIPK3-caspase 8 complex mediates atypical pro-IL-1beta processing. J Immunol. 2015;194:1938–44.

  24. 24.

    Moriwaki K, Balaji S, McQuade T, Malhotra N, Kang J, Chan FK. The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair. Immunity. 2014;41:567–78.

  25. 25.

    Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity. 2012;36:215–27.

  26. 26.

    Wong WW, Vince JE, Lalaoui N, Lawlor KE, Chau D, Bankovacki A, et al. cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood. 2014;123:2562–72.

  27. 27.

    Yatim N, Jusforgues-Saklani H, Orozco S, Schulz O, Barreira da Silva R, Reis e Sousa C, et al. RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8( + ) T cells. Science. 2015;350:328–34.

  28. 28.

    Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35.

  29. 29.

    Baldridge MT, King KY, Goodell MA. Inflammatory signals regulate hematopoietic stem cells. Trends Immunol. 2011;32:57–65.

  30. 30.

    King KY, Goodell MA. Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat Rev Immunol. 2011;11:685–92.

  31. 31.

    Manz MG, Boettcher S. Emergency granulopoiesis. Nat Rev Immunol. 2014;14:302.

  32. 32.

    Haas S, Hansson J, Klimmeck D, Loeffler D, Velten L, Uckelmann H, et al. Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell. 2015;17:422–34.

  33. 33.

    Pietras EM, Reynaud D, Kang YA, Carlin D, Calero-Nieto FJ, Leavitt AD, et al. Functionally distinct subsets of lineage-biased multipotent progenitors control blood production in normal and regenerative conditions. Cell Stem Cell. 2015;17:35–46.

  34. 34.

    Zhao JL, Ma C, O’Connell RM, Mehta A, DiLoreto R, Heath JR, et al. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell. 2014;14:445–59.

  35. 35.

    Young K, Borikar S, Bell R, Kuffler L, Philip V, Trowbridge JJ. Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging. J Exp Med. 2016;213:2259–67.

  36. 36.

    Pietras EM, Warr MR, Passegue E. Cell cycle regulation in hematopoietic stem cells. J Cell Biol. 2011;195:709–20.

  37. 37.

    Yu VW, Scadden DT. Heterogeneity of the bone marrow niche. Curr Opin Hematol. 2016;23:331–8.

  38. 38.

    Asada N, Takeishi S, Frenette PS. Complexity of bone marrow hematopoietic stem cell niche. Int J Hematol. 2017;106:45–54.

  39. 39.

    England H, Summersgill HR, Edye ME, Rothwell NJ, Brough D. Release of interleukin-1alpha or interleukin-1beta depends on mechanism of cell death. J Biol Chem. 2014;289:15942–50.

  40. 40.

    Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, et al. Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity. 2012;36:388–400.

  41. 41.

    Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99–109.

  42. 42.

    Schuettpelz LG, Borgerding JN, Christopher MJ, Gopalan PK, Romine MP, Herman AC, et al. G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling. Leukemia. 2014;28:1851–60.

  43. 43.

    Liu F, Poursine-Laurent J, Wu HY, Link DC. Interleukin-6 and the granulocyte colony-stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood. 1997;90:2583–90.

  44. 44.

    Zhang P, Iwama A, Datta MW, Darlington GJ, Link DC, Tenen DG. Upregulation of interleukin 6 and granulocyte colony-stimulating factor receptors by transcription factor CCAAT enhancer binding protein alpha (C/EBP alpha) is critical for granulopoiesis. J Exp Med. 1998;188:1173–84.

  45. 45.

    Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, et al. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity. 2012;37:1009–23.

  46. 46.

    Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010;465:793–7.

  47. 47.

    Kim J, Kim W, Le HT, Moon UJ, Tran VG, Kim HJ, et al. IL-33-induced hematopoietic stem and progenitor cell mobilization depends upon CCR2. J Immunol. 2014;193:3792–802.

  48. 48.

    Dyer KD, Percopo CM, Rosenberg HF. IL-33 promotes eosinophilia in vivo and antagonizes IL-5-dependent eosinophil hematopoiesis ex vivo. Immunol Lett. 2013;150:41–7.

  49. 49.

    Ben Baruch-Morgenstern N, Shik D, Moshkovits I, Itan M, Karo-Atar D, Bouffi C, et al. Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5-induced eosinophil development. Nat Immunol. 2014;15:36–44.

  50. 50.

    Huang Y, Guo L, Qiu J, Chen X, Hu-Li J, Siebenlist U, et al. IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat Immunol. 2015;16:161–9.

  51. 51.

    Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458:904–8.

  52. 52.

    Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005;5:375–86.

  53. 53.

    Sato T, Onai N, Yoshihara H, Arai F, Suda T, Ohteki T. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type Iinterferon–dependent exhaustion. Nat Med. 2009;15:696.

  54. 54.

    Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202:1599–611.

  55. 55.

    Snoeck HW. Interferon gamma selectively inhibits very primitive CD342 + CD38- and not more mature CD34 + CD38 + human hematopoietic progenitor cells. J Exp Med. 1994;180:1177–82.

  56. 56.

    Yang L, Dybedal I, Bryder D, Nilsson L, Sitnicka E, Sasaki Y, et al. IFN-negatively modulates self-renewal of repopulating human hemopoietic stem cells. J Immunol. 2005;174:752–7.

  57. 57.

    Zeng W, Miyazato A, Chen G, Kajigaya S, Young NS, Maciejewski JP. Interferon-gamma-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles. Blood. 2006;107:167–75.

  58. 58.

    Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol. 1995;165:538–46.

  59. 59.

    Matatall KA, Jeong M, Chen S, Sun D, Chen F, Mo Q, et al. Chronic infection depletes hematopoietic stem cells through stress-induced terminal differentiation. Cell Rep. 2016;17:2584–95.

  60. 60.

    Matatall KA, Shen CC, Challen GA, King KY. Type II interferon promotes differentiation of myeloid-biased hematopoietic stem cells. Stem Cells. 2014;32:3023–30.

  61. 61.

    Young NS, Scheinberg P, Calado RT. Aplastic anemia. Curr Opin Hematol. 2008;15:162–8.

  62. 62.

    Lin FC, Karwan M, Saleh B, Hodge DL, Chan T, Boelte KC, et al. IFN-gamma causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation. Blood. 2014;124:3699–708.

  63. 63.

    Belyaev NN, Brown DE, Diaz AI, Rae A, Jarra W, Thompson J, et al. Induction of an IL7-R( + )c-Kit(hi) myelolymphoid progenitor critically dependent on IFN-gamma signaling during acute malaria. Nat Immunol. 2010;11:477–85.

  64. 64.

    Broxmeyer HE, Williams DE, Lu L, Cooper S, Anderson SL, Beyer GS, et al. The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma. J Immunol. 1986;136:4487–95.

  65. 65.

    Rusten LS, Jacobsen FW, Lesslauer W, Loetscher H, Smeland EB, Jacobsen SE. Bifunctional effects of tumor necrosis factor alpha (TNF alpha) on the growth of mature and primitive human hematopoietic progenitor cells: involvement of p55 and p75 TNF receptors. Blood. 1994;83:3152–9.

  66. 66.

    Dybedal I, Bryder D, Fossum A, Rusten LS, Jacobsen SE. Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells. Blood. 2001;98:1782–91.

  67. 67.

    Zhang Y, Harada A, Bluethmann H, Wang JB, Nakao S, Mukaida N, et al. Tumor necrosis factor (TNF) is a physiologic regulator of hematopoietic progenitor cells: increase of early hematopoietic progenitor cells in TNF receptor p55-deficient mice in vivo and potent inhibition of progenitor cell proliferation by TNF alpha in vitro. Blood. 1995;86:2930–7.

  68. 68.

    Jacobsen FW, Rothe M, Rusten L, Goeddel DV, Smeland EB, Veiby OP, et al. Role of the 75-kDa tumor necrosis factor receptor: inhibition of early hematopoiesis. Proc Natl Acad Sci USA. 1994;91:10695–9.

  69. 69.

    Jacobsen SE, Ruscetti FW, Dubois CM, Keller JR. Tumor necrosis factor alpha directly and indirectly regulates hematopoietic progenitor cell proliferation: role of colony-stimulating factor receptor modulation. J Exp Med. 1992;175:1759–72.

  70. 70.

    Rezzoug F, Huang Y, Tanner MK, Wysoczynski M, Schanie CL, Chilton PM, et al. TNF- is critical to facilitate hemopoietic stem cell engraftment and function. J Immunol. 2007;180:49–57.

  71. 71.

    Pearl-Yafe M, Mizrahi K, Stein J, Yolcu ES, Kaplan O, Shirwan H, et al. Tumor necrosis factor receptors support murine hematopoietic progenitor function in the early stages of engraftment. Stem Cells. 2010;28:1270–80.

  72. 72.

    Pronk CJ, Veiby OP, Bryder D, Jacobsen SE. Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors. J Exp Med. 2011;208:1563–70.

  73. 73.

    Roderick JE, Hermance N, Zelic M, Simmons MJ, Polykratis A, Pasparakis M, et al. Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. Proc Natl Acad Sci USA. 2014;111:14436–41.

  74. 74.

    Rickard JA, O’Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014;157:1175–88.

  75. 75.

    Tesio M, Tang Y, Mudder K, Saini M, von Paleske L, Macintyre E, et al. Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38 MAPK pathway. J Exp Med. 2015;212:525–38.

  76. 76.

    Sioud M, Floisand Y, Forfang L, Lund-Johansen F. Signaling through toll-like receptor 7/8 induces the differentiation of human bone marrow CD34 + progenitor cells along the myeloid lineage. J Mol Biol. 2006;364:945–54.

  77. 77.

    Nagai Y, Garrett KP, Ohta S, Bahrun U, Kouro T, Akira S, et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity. 2006;24:801–12.

  78. 78.

    Esplin BL, Shimazu T, Welner RS, Garrett KP, Nie L, Zhang Q, et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol. 2011;186:5367–75.

  79. 79.

    Rodriguez S, Chora A, Goumnerov B, Mumaw C, Goebel WS, Fernandez L, et al. Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood. 2009;114:4064–76.

  80. 80.

    Takizawa H, Regoes RR, Boddupalli CS, Bonhoeffer S, Manz MG. Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation. J Exp Med. 2011;208:273–84.

  81. 81.

    Clapes T, Lefkopoulos S, Trompouki E. Stress and non-stress roles of inflammatory signals during HSC emergence and maintenance. Front Immunol. 2016;7:487

  82. 82.

    Pietras EM. Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood. 2017;130:1693–8.

  83. 83.

    Laurenti E, Doulatov S, Zandi S, Plumb I, Chen J, April C, et al. The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment. Nat Immunol. 2013;14:756–63.

  84. 84.

    Wilson NK, Kent DG, Buettner F, Shehata M, Macaulay IC, Calero-Nieto FJ, et al. Combined single-cell functional and gene expression analysis resolves heterogeneity within stem cell populations. Cell Stem Cell. 2015;16:712–24.

  85. 85.

    Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature. 2015;518:542–6.

  86. 86.

    Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514:322–7.

  87. 87.

    Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q, et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell. 2014;15:507–22.

  88. 88.

    Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351:aab2116.

  89. 89.

    Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL, et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154:1112–26.

  90. 90.

    Rebel VI, Hartnett S, Hill GR, Lazo-Kallanian SB, Ferrara JL, Sieff CA. Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level. J Exp Med. 1999;190:1493–504.

  91. 91.

    Ichii M, Shimazu T, Welner RS, Garrett KP, Zhang Q, Esplin BL, et al. Functional diversity of stem and progenitor cells with B-lymphopoietic potential. Immunol Rev. 2010;237:10–21.

  92. 92.

    Espin-Palazon R, Stachura DL, Campbell CA, Garcia-Moreno D, Del Cid N, Kim AD, et al. Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell. 2014;159:1070–85.

  93. 93.

    Li Y, Esain V, Teng L, Xu J, Kwan W, Frost IM, et al. Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes Dev. 2014;28:2597–612.

  94. 94.

    Sawamiphak S, Kontarakis Z, Stainier DY. Interferon gamma signaling positively regulates hematopoietic stem cell emergence. Dev Cell. 2014;31:640–53.

  95. 95.

    He Q, Zhang C, Wang L, Zhang P, Ma D, Lv J, et al. Inflammatory signaling regulates hematopoietic stem and progenitor cell emergence in vertebrates. Blood. 2015;125:1098–106.

  96. 96.

    Stachura DL, Svoboda O, Campbell CA, Espin-Palazon R, Lau RP, Zon LI, et al. The zebrafish granulocyte colony-stimulating factors (Gcsfs): 2 paralogous cytokines and their roles in hematopoietic development and maintenance. Blood. 2013;122:3918–28.

  97. 97.

    De La Garza A, Sinha A, Bowman TV. Concise review: hematopoietic stem cell origins: lessons from embryogenesis for improving regenerative medicine. Stem Cells Transl Med. 2017;6:60–7.

  98. 98.

    Orelio C, Haak E, Peeters M, Dzierzak E. Interleukin-1-mediated hematopoietic cell regulation in the aorta-gonad-mesonephros region of the mouse embryo. Blood. 2008;112:4895–904.

  99. 99.

    Robin C, Ottersbach K, Durand C, Peeters M, Vanes L, Tybulewicz V, et al. An unexpected role for IL-3 in the embryonic development of hematopoietic stem cells. Dev Cell. 2006;11:171–80.

  100. 100.

    Kim AD, Melick CH, Clements WK, Stachura DL, Distel M, Panakova D, et al. Discrete Notch signaling requirements in the specification of hematopoietic stem cells. EMBO J. 2014;33:2363–73.

  101. 101.

    Liongue C, Hall CJ, O’Connell BA, Crosier P, Ward AC. Zebrafish granulocyte colony-stimulating factor receptor signaling promotes myelopoiesis and myeloid cell migration. Blood. 2009;113:2535–46.

  102. 102.

    Pietras EM, Mirantes-Barbeito C, Fong S, Loeffler D, Kovtonyuk LV, Zhang S, et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol. 2016;18:607–18.

  103. 103.

    Chen Y, Zou Z, Wu Z, Zhao Z, Luo X, Xie C, et al. TNF-alpha-induced programmed cell death in the pathogenesis of acquired aplastic anemia. Expert Rev Hematol. 2015;8:515–26.

  104. 104.

    Xiao Y, Li H, Zhang J, Volk A, Zhang S, Wei W, et al. TNF-alpha/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations. Blood. 2011;118:6057–67.

  105. 105.

    Xin J, Breslin P, Wei W, Li J, Gutierrez R, Cannova J, et al. Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice. Haematologica. 2017;102:295–307.

  106. 106.

    Denkinger MD, Leins H, Schirmbeck R, Florian MC, Geiger H. HSC aging and senescent immune remodeling. Trends Immunol. 2015;36:815–24.

  107. 107.

    Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.

  108. 108.

    Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Natl Acad Sci USA. 2009;106:17031–6.

  109. 109.

    Akunuru S, Geiger H. Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med. 2016;22:701–12.

  110. 110.

    Ergen AV, Boles NC, Goodell MA. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood. 2012;119:2500–9.

  111. 111.

    Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12:413–25.

  112. 112.

    Zambetti NA, Ping Z, Chen S, Kenswil KJG, Mylona MA, Sanders MA, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell. 2016;19:613–27.

  113. 113.

    Chen L, Chen W, Mysliwski M, Serio J, Ropa J, Abulwerdi FA, et al. Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition. Leukemia. 2015;29:1290–300.

  114. 114.

    Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M, Garg T, et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell. 2013;13:285–99.

  115. 115.

    Carey A, DKt Edwards, Eide CA, Newell L, Traer E, Medeiros BC, et al. Identification of interleukin-1 by functional screening as a key mediator of cellular expansion and disease progression in acute myeloid leukemia. Cell Rep. 2017;18:3204–18.

  116. 116.

    Welner RS, Amabile G, Bararia D, Czibere A, Yang H, Zhang H, et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell. 2015;27:671–81.

  117. 117.

    Ganan-Gomez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29:1458–69.

  118. 118.

    Reynaud D, Pietras E, Barry-Holson K, Mir A, Binnewies M, Jeanne M, et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development. Cancer Cell. 2011;20:661–73.

  119. 119.

    Korn C, Mendez-Ferrer S. Myeloid malignancies and the microenvironment. Blood. 2017;129:811–22.

  120. 120.

    Rozovski U, Keating MJ, Estrov Z. Targeting inflammatory pathways in chronic lymphocytic leukemia. Crit Rev Oncol Hematol. 2013;88:655–66.

  121. 121.

    Schepers K, Campbell TB, Passegue E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell. 2015;16:254–67.

  122. 122.

    Caligaris-Cappio F. Inflammation, the microenvironment and chronic lymphocytic leukemia. Haematologica. 2011;96:353–5.

  123. 123.

    Herault A, Binnewies M, Leong S, Calero-Nieto FJ, Zhang SY, Kang YA, et al. Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis. Nature. 2017;544:53–8.

  124. 124.

    Höckendorf U, Yabal M, Herold T, Munkhbaatar E, Rott S, Jilg S, et al. RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells. Cancer Cell. 2016;30:75–91.

  125. 125.

    Liu P, Xu B, Shen W, Zhu H, Wu W, Fu Y, et al. Dysregulation of TNF alpha-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1. Leukemia. 2012;26:1293–300.

  126. 126.

    Kikuchi M, Kuroki S, Kayama M, Sakaguchi S, Lee KK, Yonehara S. Protease activity of procaspase-8 is essential for cell survival by inhibiting both apoptotic and nonapoptotic cell death dependent on receptor-interacting protein kinase 1 (RIP1) and RIP3. J Biol Chem. 2012;287:41165–73.

  127. 127.

    Cerhan JR, Ansell SM, Fredericksen ZS, Kay NE, Liebow M, Call TG, et al. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma. Blood. 2007;110:4455–63.

  128. 128.

    Nugues AL, El Bouazzati H, Hetuin D, Berthon C, Loyens A, Bertrand E, et al. RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. Cell Death Dis. 2014;5:e1384.

  129. 129.

    Katsumura KR, Ong IM, DeVilbiss AW, Sanalkumar R, Bresnick EH. GATA factor-dependent positive-feedback circuit in acute myeloid leukemia cells. Cell Rep. 2016;16:2428–41.

  130. 130.

    Su SJ, Yeh YT, Su SH, Chang KL, Shyu HW, Chen KM, et al. Biochanin a promotes osteogenic but inhibits adipogenic differentiation: evidence with primary adipose-derived stem cells. Evid Based Complement Altern Med. 2013;2013:846039.

  131. 131.

    Yang J, Ikezoe T, Nishioka C, Nobumoto A, Yokoyama A. IL-1beta inhibits self-renewal capacity of dormant CD34( + )/CD38(-) acute myelogenous leukemia cells in vitro and in vivo. Int J Cancer. 2013;133:1967–81.

  132. 132.

    Liang K, Volk AG, Haug JS, Marshall SA, Woodfin AR, Bartom ET, et al. Therapeutic targeting of MLL degradation pathways in MLL-rearranged leukemia. Cell. 2017;168:59–72.

  133. 133.

    Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, et al. Autocrine TNF alpha signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell. 2007;12:445–56.

  134. 134.

    Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, et al. IAP antagonists target cIAP1 to induce TNF alpha-dependent apoptosis. Cell. 2007;131:682–93.

  135. 135.

    Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNF alpha-dependent apoptosis. Cell. 2007;131:669–81.

  136. 136.

    Safferthal C, Rohde K, Fulda S. Therapeutic targeting of necroptosis by Smac mimetic bypasses apoptosis resistance in acute myeloid leukemia cells. Oncogene. 2017;36:1487–502.

  137. 137.

    Chromik J, Safferthal C, Serve H, Fulda S. Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis. Cancer Lett. 2014;344:101–9.

  138. 138.

    Steinhart L, Belz K, Fulda S. Smac mimetic and demethylating agents synergistically trigger cell death in acute myeloid leukemia cells and overcome apoptosis resistance by inducing necroptosis. Cell Death Dis. 2013;4:e802.

  139. 139.

    Steinwascher S, Nugues AL, Schoeneberger H, Fulda S. Identification of a novel synergistic induction of cell death by Smac mimetic and HDAC inhibitors in acute myeloid leukemia cells. Cancer Lett. 2015;366:32–43.

  140. 140.

    Gerges S, Rohde K, Fulda S. Cotreatment with Smac mimetics and demethylating agents induces both apoptotic and necroptotic cell death pathways in acute lymphoblastic leukemia cells. Cancer Lett. 2016;375:127–32.

  141. 141.

    Schenk B, Fulda S. Reactive oxygen species regulate Smac mimetic/TNF alpha-induced necroptotic signaling and cell death. Oncogene. 2015;34:5796–806.

  142. 142.

    Rohde K, Kleinesudeik L, Roesler S, Lowe O, Heidler J, Schroder K, et al. A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis. Cell Death Differ. 2017;24:83–97.

  143. 143.

    Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M, Tanzer MC, et al. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med. 2016;8:339ra69.

  144. 144.

    Lalaoui N, Hanggi K, Brumatti G, Chau D, Nguyen NY, Vasilikos L, et al. Targeting p38 or MK2 enhances the anti-leukemic activity of Smac-mimetics. Cancer Cell. 2016;29:145–58.

  145. 145.

    McComb S, Aguade-Gorgorio J, Harder L, Marovca B, Cario G, Eckert C, et al. Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL. Sci Transl Med. 2016;8:339ra70.

  146. 146.

    Richmond J, Robbins A, Evans K, Beck D, Kurmasheva RT, Billups CA, et al. Acute sensitivity of Ph-like acute lymphoblastic leukemia to the SMAC-mimetic birinapant. Cancer Res. 2016;76:4579–91.

  147. 147.

    Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and mincle-induced immune suppression. Nature. 2016;532:245–9.

  148. 148.

    Aaes TL, Kaczmarek A, Delvaeye T, De Craene B, De Koker S, Heyndrickx L, et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep. 2016;15:274–87.

Download references

Author information


  1. Medical Department III of Hematology and Oncology, Klinikum Rechts der Isar, Technische Universität München, 81675, München, Germany

    • Philipp J. Jost
    •  & Ulrike Höckendorf
  2. German Consortium for Translational Cancer Research (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Philipp J. Jost


  1. Search for Philipp J. Jost in:

  2. Search for Ulrike Höckendorf in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Philipp J. Jost.

About this article

Publication history






Article notes

Edited by F. Pentimalli