Skip to main content
SpringerLink
Log in

Cellular and Molecular State of Myeloid Leukemia Stem Cells

  • Chapter
  • First Online:
Leukemia Stem Cells in Hematologic Malignancies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1143))

Abstract

Leukemia stem cells (LSCs) are leukemia-initiating population with the capacity to self-renew, differentiate, and stay quiescent. Human hematopoietic malignancies such as chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are derived from this cell population. LSCs are also responsible for disease relapse due to its resistance to drug treatment. This rare cell population is phenotypically and functionally heterogeneous. Increasing evidence indicates that this heterogeneous cellular state of LSCs might determine the different drug sensitivity and is the major reason for disease relapse. In here, focusing on myeloid leukemia stem cells, we describe the biological features including cellular and molecular state, heterogeneity of LSCs, and the dynamic cross talk between LSCs and bone marrow microenvironment. These specific features of LSCs highlight the dynamic cellular state of LSCs, and further exploring on it might provide potential therapeutic targets that are important for eliminating LSCs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Till JE, McCulloch EA, Siminovitch L (1964) A stochastic model of stem cell proliferation, based on the growth of spleen Colony-forming cells. Proc Natl Acad Sci U S A 51:29–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Korn AP, Henkelman RM, Ottensmeyer FP, Till JE (1973) Investigations of a stochastic model of haemopoiesis. Exp Hematol 1(6):362–375

    CAS  PubMed  Google Scholar 

  3. Visvader JE, Lindeman GJ (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10(6):717–728

    Article  CAS  PubMed  Google Scholar 

  4. Bruce WR, Van Der Gaag H (1963) A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199:79–80

    Article  CAS  PubMed  Google Scholar 

  5. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    Article  CAS  PubMed  Google Scholar 

  6. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737

    Article  CAS  PubMed  Google Scholar 

  7. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828

    CAS  PubMed  Google Scholar 

  9. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037

    Article  CAS  PubMed  Google Scholar 

  10. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    Article  CAS  PubMed  Google Scholar 

  11. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121(6):823–835

    Article  CAS  PubMed  Google Scholar 

  12. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON (2010) Identification of a cell of origin for human prostate cancer. Science 329(5991):568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Melo JV, Barnes DJ (2007) Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 7(6):441–453

    Article  CAS  PubMed  Google Scholar 

  14. Wang JC, Dick JE (2005) Cancer stem cells: lessons from leukemia. Trends Cell Biol 15(9):494–501

    Article  CAS  PubMed  Google Scholar 

  15. Wong S, Witte ON (2004) The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 22:247–306

    Article  CAS  PubMed  Google Scholar 

  16. Savona M, Talpaz M (2008) Getting to the stem of chronic myeloid leukaemia. Nat Rev Cancer 8(5):341–350

    Article  CAS  PubMed  Google Scholar 

  17. Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5(3):172–183

    Article  CAS  PubMed  Google Scholar 

  18. Dohner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373(12):1136–1152

    Article  PubMed  CAS  Google Scholar 

  19. Dick JE (2005) Acute myeloid leukemia stem cells. Ann N Y Acad Sci 1044:1–5

    Article  PubMed  Google Scholar 

  20. Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S (2006) Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci U S A 103(45):16870–16875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99(1):319–325

    Article  CAS  PubMed  Google Scholar 

  22. Wisniewski D, Affer M, Willshire J, Clarkson B (2011) Further phenotypic characterization of the primitive lineage- CD34+CD38-CD90+CD45RA- hematopoietic stem cell/progenitor cell sub-population isolated from cord blood, mobilized peripheral blood and patients with chronic myelogenous leukemia. Blood Cancer J 1(9):e36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herrmann H, Sadovnik I, Cerny-Reiterer S, Rulicke T, Stefanzl G, Willmann M et al (2014) Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood 123(25):3951–3962

    Article  CAS  PubMed  Google Scholar 

  24. Jan M, Chao MP, Cha AC, Alizadeh AA, Gentles AJ, Weissman IL et al (2011) Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci U S A 108(12):5009–5014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kikushige Y, Miyamoto T, Yuda J, Jabbarzadeh-Tabrizi S, Shima T, Takayanagi S et al (2015) A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 17(3):341–352

    Article  CAS  PubMed  Google Scholar 

  26. Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H et al (2010) TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 7(6):708–717

    Article  CAS  PubMed  Google Scholar 

  27. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr et al (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138(2):286–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G et al (2005) Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106(13):4086–4092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S et al (2010) Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med 2(17):17ra9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Thomas D, Majeti R (2017) Biology and relevance of human acute myeloid leukemia stem cells. Blood 129(12):1577–1585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S et al (2011) Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19(1):138–152

    Article  CAS  PubMed  Google Scholar 

  32. Bowman RL, Busque L, Levine RL (2018) Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22(2):157–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F et al (2016) Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med 22(7):792–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer FB et al (2017) Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell 169(5):807–23 e19

    Article  CAS  PubMed  Google Scholar 

  35. Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, Verovskaya EV et al (2017) Autophagy maintains the metabolism and function of young and old stem cells. Nature 543(7644):205–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E et al (2013) Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12(1):49–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Signer RA, Magee JA, Salic A, Morrison SJ (2014) Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509(7498):49–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  39. Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN et al (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7(3):380–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jones CL, Stevens BM, D’Alessandro A, Reisz JA, Culp-Hill R, Nemkov T et al (2018) Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell 34(5):724–40 e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M et al (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12(3):329–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kuntz EM, Baquero P, Michie AM, Dunn K, Tardito S, Holyoake TL et al (2017) Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med 23(10):1234–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaelin WG Jr, McKnight SL (2013) Influence of metabolism on epigenetics and disease. Cell 153(1):56–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C et al (2017) BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551(7680):384–388

    Article  CAS  PubMed  Google Scholar 

  45. Zhang H, Li H, Ho N, Li D, Li S (2012) Scd1 plays a tumor-suppressive role in survival of leukemia stem cells and the development of chronic myeloid leukemia. Mol Cell Biol 32(10):1776–1787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J et al (2017) Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 545(7655):500–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Garraway LA, Lander ES (2013) Lessons from the cancer genome. Cell 153(1):17–37

    Article  CAS  PubMed  Google Scholar 

  48. Chi P, Allis CD, Wang GG (2010) Covalent histone modifications – miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10(7):457–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xie H, Peng C, Huang J, Li BE, Kim W, Smith EC et al (2016) Chronic myelogenous leukemia- initiating cells require Polycomb group protein EZH2. Cancer Discov 6(11):1237–1247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Scott MT, Korfi K, Saffrey P, Hopcroft LE, Kinstrie R, Pellicano F et al (2016) Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition. Cancer Discov 6(11):1248–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou J, Nie D, Li J, Du X, Lu Y, Li Y et al (2018) PTEN is fundamental for elimination of leukemia stem cells mediated by GSK126 targeting EZH2 in chronic myelogenous leukemia. Clin Cancer Res 24(1):145–157

    Article  CAS  PubMed  Google Scholar 

  52. Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M et al (2018) Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med 24(12):1859–1866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM et al (2007) Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12(6):528–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458(7239):776–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y et al (2010) TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463(7281):676–680

    Article  CAS  PubMed  Google Scholar 

  56. Holyoake TL, Vetrie D (2017) The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood 129(12):1595–1606

    Article  CAS  PubMed  Google Scholar 

  57. Cortes J, O’Brien S, Kantarjian H (2004) Discontinuation of imatinib therapy after achieving a molecular response. Blood 104(7):2204–2205

    Article  CAS  PubMed  Google Scholar 

  58. Hamilton AHG, Schemionek M, Zhang B, Myssina S, Allan EK, Nicolini FE, Müller-Tidow C, Bhatia R, Brunton VG, Koschmieder S, Holyoake TL (2012) Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 119:1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ (2011) Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 121(1):396–409

    Article  CAS  PubMed  Google Scholar 

  60. Chen Y, Hu Y, Zhang H, Peng C, Li S (2009) Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet 41(7):783–792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang H, Peng C, Hu Y, Li H, Sheng Z, Chen Y et al (2012) The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nat Genet 44(8):861–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K et al (2007) Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1(2):218–229

    Article  CAS  PubMed  Google Scholar 

  63. Benz C, Copley MR, Kent DG, Wohrer S, Cortes A, Aghaeepour N et al (2012) Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 10(3):273–283

    Article  CAS  PubMed  Google Scholar 

  64. Zhou F, Li X, Wang W, Zhu P, Zhou J, He W et al (2016) Tracing haematopoietic stem cell formation at single-cell resolution. Nature 533(7604):487–492

    Article  CAS  PubMed  Google Scholar 

  65. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F et al (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11(11):1029–1035

    Article  CAS  PubMed  Google Scholar 

  66. Chomel JC, Bonnet ML, Sorel N, Bertrand A, Meunier MC, Fichelson S et al (2011) Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood 118(13):3657–3660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA et al (2010) Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 24(10):1719–1724

    Article  CAS  PubMed  Google Scholar 

  68. Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK et al (2012) Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 119(6):1501–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang B, Li L, Ho Y, Li M, Marcucci G, Tong W et al (2016) Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells. J Clin Invest 126(3):975–991

    Article  PubMed  PubMed Central  Google Scholar 

  70. Giustacchini A, Thongjuea S, Barkas N, Woll PS, Povinelli BJ, Booth CAG et al (2017) Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med 23(6):692–702

    Article  CAS  PubMed  Google Scholar 

  71. Li S, Mason CE, Melnick A (2016) Genetic and epigenetic heterogeneity in acute myeloid leukemia. Curr Opin Genet Dev 36:100–106

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Paguirigan AL, Smith J, Meshinchi S, Carroll M, Maley C, Radich JP (2015) Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Sci Transl Med 7(281):281re2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150(2):264–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al (2012) Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481(7382):506–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al (2014) Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506(7488):328–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al (2014) Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20(12):1472–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gerrits A, Dykstra B, Kalmykowa OJ, Klauke K, Verovskaya E, Broekhuis MJ et al (2010) Cellular barcoding tool for clonal analysis in the hematopoietic system. Blood 115(13):2610–2618

    Article  CAS  PubMed  Google Scholar 

  78. Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ et al (2014) Clonal dynamics of native haematopoiesis. Nature 514(7522):322–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Etzrodt M, Endele M, Schroeder T (2014) Quantitative single-cell approaches to stem cell research. Cell Stem Cell 15(5):546–558

    Article  CAS  PubMed  Google Scholar 

  80. Drissen R, Buza-Vidas N, Woll P, Thongjuea S, Gambardella A, Giustacchini A et al (2016) Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing. Nat Immunol 17(6):666–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhao M, Li L (2016) Dissecting the bone marrow hematopoietic stem cell niches. Cell Res 26:975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132(4):598–611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6(2):93–106

    Article  CAS  PubMed  Google Scholar 

  84. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846

    Article  CAS  PubMed  Google Scholar 

  85. Kobayashi H, Butler JM, O’Donnell R, Kobayashi M, Ding BS, Bonner B et al (2010) Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat Cell Biol 12(11):1046–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT et al (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6(3):251–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Acar M, Kocherlakota KS, Murphy MM, Peyer JG, Oguro H, Inra CN et al (2015) Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526(7571):126–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S et al (2011) Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147(5):1146–1158

    Article  CAS  PubMed  Google Scholar 

  90. Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC et al (2014) Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 20(11):1321–1326

    Article  CAS  PubMed  Google Scholar 

  91. Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481(7382):457–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hoggatt J, Kfoury Y, Scadden DT (2016) Hematopoietic stem cell niche in health and disease. Annu Rev Pathol 11:555–581

    Article  CAS  PubMed  Google Scholar 

  93. Schepers K, Campbell TB, Passegue E (2015) Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 16(3):254–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D, Means TK et al (2005) In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435(7044):969–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Krause DS, Lazarides K, Lewis JB, von Andrian UH, Van Etten RA (2014) Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood 123(9):1361–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Krause DS, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP et al (2013) Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med 19(11):1513–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA et al (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464(7290):852–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N et al (2014) Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 506(7487):240–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Medyouf H, Mossner M, Jann JC, Nolte F, Raffel S, Herrmann C et al (2014) Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 14(6):824–837

    Article  CAS  PubMed  Google Scholar 

  100. Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU et al (2012) Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21(4):577–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P et al (2008) Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14(3):238–249

    Article  CAS  PubMed  Google Scholar 

  102. Irvine DA, Zhang B, Kinstrie R, Tarafdar A, Morrison H, Campbell VL et al (2016) Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep 6:25476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Irvine DA, Copland M (2012) Targeting hedgehog in hematologic malignancy. Blood 119(10):2196–2204

    Article  CAS  PubMed  Google Scholar 

  104. Prost S, Relouzat F, Spentchian M, Ouzegdouh Y, Saliba J, Massonnet G et al (2015) Erosion of the chronic myeloid leukaemia stem cell pool by PPARgamma agonists. Nature 525(7569):380–383

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Shaoguang Li from University of Massachusetts Medical School, USA, and all the members of our laboratory for critically reading this manuscript. This work is supported by grants from the National Key Research and Development Program of China (2017YFA0505600), the National Natural Science Foundation of China (81722003, 81870124), the Wuhan Science and Technology Program for Application and Basic Research Project (2018060401011325), and the Hubei Provincial Natural Science Foundation for Creative Research Group (2018CFA018).

Author information

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China

    Xueqin Xie, Mengdie Feng, Qifan Wang, Jiazhen Wang, Rong Yin, Yicun Li & Haojian Zhang

  2. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China

    Xueqin Xie, Mengdie Feng, Qifan Wang, Jiazhen Wang, Rong Yin & Haojian Zhang

Authors
  1. Xueqin Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mengdie Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qifan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiazhen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yicun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haojian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haojian Zhang .

Editor information

Editors and Affiliations

  1. Medical Research Institute, Wuhan University, Wuhan, Hubei, China

    Haojian Zhang

  2. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Shaoguang Li

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Xie, X. et al. (2019). Cellular and Molecular State of Myeloid Leukemia Stem Cells. In: Zhang, H., Li, S. (eds) Leukemia Stem Cells in Hematologic Malignancies. Advances in Experimental Medicine and Biology, vol 1143. Springer, Singapore. https://doi.org/10.1007/978-981-13-7342-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation