Chapter 50 : Myeloid Cell Origins, Differentiation, and Clinical Implications

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The hematopoietic stem cell (HSC) is a multipotent stem cell that resides in the bone marrow and has the ability to form all of the cells of the blood and immune system. As the quintessential stem cell, it has the ability to self-replicate and differentiate into progeny of multiple lineages. Hematopoiesis describes the process of differentiating from HSCs to mature, functional cell types of the blood lineages. The existence of HSCs was first hypothesized following early experiments that demonstrated that animals receiving lethal doses of irradiation could be rescued by transplanting unfractionated bone marrow cells ( ). The transplanted cells repopulated the bone marrow of the recipients and gave rise to all the cells of the blood. In accordance with this observation, in 1961 Till and McCulloch showed that unfractionated bone marrow cells were able to generate mixed hematopoietic (myeloid and erythroid) colonies in the spleens of lethally irradiated mice ( ). They subsequently demonstrated that these colonies were formed by single cells that were capable of multilineage differentiation ( ). Given the limitations in technology at the time, they were unable to purify these cells further, and the experiment that showed clonal origin of spleen colonies did not include lymphoid cells ( ), although a later experiment did ( ). Years later, with the advent of monoclonal antibodies and fluorescence-activated cell sorting, these cells could be further characterized, purified, and evaluated in functional assays. Studies have now conclusively demonstrated that HSCs are a rare population of cells that give rise to all of the cells comprising the two main branches of the hematopoietic lineage: the myeloid arm and the lymphoid arm. In mice, all long-term HSCs (LT-HSCs) are Hoxb5 ( ) and located in the central marrow attached to the abluminal side of venous sinusoids.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 1

General organization of the hematopoietic lineage in mice and humans. The HSC can give rise to all of the cells of the blood and immune system, with multiple stepwise intermediates arising before developing into fully differentiated cells. The CMP and the CLP give rise to the two mains arms of the hematopoietic hierarchy. The CMP can give rise to all myeloid cells. Conventional surface markers for purifying each population are indicated for both mice and humans. GP, granulocyte progenitor; MacP, macrophage progenitor. Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 2

Purification of the first HSCs. (A) Representative examples of purified HSCs as visualized by microscopy after hematoxylin staining. (B) Myeloerythroid colonies in the spleen formed by the injection of purified HSCs into lethally irradiated mice. (C) A single lymphoid colony in the thymus formed by the injection of purified HSCs into lethally irradiated mice. (D) Fluorescence-activated cell sorting depicting HSCs as Thy-1Sca-1. Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 3

RNA expression pattern of IL-7Rα throughout the murine hematopoietic lineage. IL-7Rα is a critical surface molecule that helps distinguish the lymphoid arm of the hematopoietic system from HSCs, progenitors, and myeloid cells. Each box represents a different hematopoietic subpopulation. Blue indicates lower expression; pink indicates higher expression. Analysis performed using Gene Expression Commons ( ). BM, bone marrow; Spl, spleen; GMLP, granulocyte/macrophage/lymphoid progenitor subset; p, pre-; s, strict; Plt, platelet; Ery, erythrocyte; Gra, granulocyte; Mono, monocyte; BLP, earliest B-lymphoid progenitor; Fr, B cell subset fraction; T1B, T1 B cell; T2B, T2 B cell; MzB, marginal zone B cell; FoB, follicular B cell; iNK, intermediate NK cell; DN, double negative T cell subset; DP, double positive T cell subset. CD4 and CD8 populations represent mature T cells.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 4

GMP frequency is decreased in low-risk MDS. Representative example of how hematopoietic progenitor cell populations can be altered in states of disease. (A) Frequency of GMPs out of total myeloid progenitors in normal, low-risk MDS and non-MDS diseased bone marrow samples. (B) Frequency of GMPs out of total lineage-negative bone marrow mononuclear cells in normal and low-risk MDS bone marrow samples. Asterisks indicate statistically significant differences: * < 10–13, ** < 10–10, *** < 0.0006. Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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Figure 5

CD47-blocking therapies are effective in preclinical models of human cancer. Xenograft studies of mice engrafted with human AML samples that were then treated with anti-CD47 antibodies. (A) Anti-CD47 antibody treatment decreases leukemia burden, as assessed by the percent of human chimerism in the bone marrow (BM) after 14 days of treatment. (B) Bone marrow histology showing leukemia infiltration in control mice (top left, bottom left), and eradication of disease in mice treated with anti-CD47 antibodies (top middle, bottom middle). In some mice with residual tumor burden following treatment with anti-CD47 antibodies (top right, bottom right), macrophages could be seen in the bone marrow engulfing leukemia cells (black arrows). Reprinted from reference , with permission.

Citation: Weiskopf K, Schnorr P, Pang W, Chao M, Chhabra A, Seita J, Feng M, Weissman I. 2017. Myeloid Cell Origins, Differentiation, and Clinical Implications, p 857-875. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0031-2016
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1. Ford CE,, Hamerton JL,, Barnes DW,, Loutit JF . 1956. Cytological identification of radiation-chimaeras. Nature 177 : 452 454.
2. Till JE,, McCulloch EA . 1961. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14 : 213 222.
3. Becker AJ,, McCulloch EA,, Till JE . 1963. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197 : 452 454.
4. Wu AM,, Till JE,, Siminovitch L,, McCulloch EA . 1968. Cytological evidence for a relationship between normal hemotopoietic colony-forming cells and cells of the lymphoid system. J Exp Med 127 : 455 464.
5. Chen JY,, Miyanishi M,, Wang SK,, Yamazaki S,, Sinha R,, Kao KS,, Seita J,, Sahoo D,, Nakauchi H,, Weissman IL . 2016. Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 530 : 223 227.
6. Adolfsson J,, Borge OJ,, Bryder D,, Theilgaard-Mönch K,, Astrand-Grundström I,, Sitnicka E,, Sasaki Y,, Jacobsen SE . 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.
7. Christensen JL,, Weissman IL . 2001. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci U S A 98 : 14541 14546.
8. Kiel MJ,, Yilmaz OH,, Iwashita T,, Yilmaz OH,, Terhorst C,, Morrison SJ . 2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121 : 1109 1121.
9. Morrison SJ,, Wandycz AM,, Hemmati HD,, Wright DE,, Weissman IL . 1997. Identification of a lineage of multipotent hematopoietic progenitors. Development 124 : 1929 1939.
10. Spangrude GJ,, Heimfeld S,, Weissman IL . 1988. Purification and characterization of mouse hematopoietic stem cells. Science 241 : 58 62.
11. Smith LG,, Weissman IL,, Heimfeld S . 1991. Clonal analysis of hematopoietic stem-cell differentiation in vivo . Proc Natl Acad Sci U S A 88 : 2788 2792.
12. Ikuta K,, Ingolia DE,, Friedman J,, Heimfeld S,, Weissman IL . 1991. Mouse hematopoietic stem cells and the interaction of c-kit receptor and steel factor. Int J Cell Cloning 9 : 451 460.
13. Czechowicz A,, Kraft D,, Weissman IL,, Bhattacharya D . 2007. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 318 : 1296 1299.
14. Chhabra A,, Ring AM,, Weiskopf K,, Schnorr PJ,, Gordon S,, Le AC,, Kwon HS,, Ring NG,, Volkmer J,, Ho PY,, Tseng S,, Weissman IL,, Shizuru JA . 2016. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci Transl Med 8 : 351ra105. doi:10.1126/scitranslmed.aae0501.
15. Morrison SJ,, Weissman IL . 1994. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1 : 661 673.
16. Sun J,, Ramos A,, Chapman B,, Johnnidis JB,, Le L,, Ho YJ,, Klein A,, Hofmann O,, Camargo FD . 2014. Clonal dynamics of native haematopoiesis. Nature 514 : 322 327.
17. Kondo M,, Weissman IL,, Akashi K . 1997. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91 : 661 672.
18. Akashi K,, Traver D,, Miyamoto T,, Weissman IL . 2000. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404 : 193 197.
19. Warren L,, Bryder D,, Weissman IL,, Quake SR . 2006. Transcription factor profiling in individual hematopoietic progenitors by digital RT-PCR. Proc Natl Acad Sci U S A 103 : 17807 17812.
20. Paul F,, Arkin Y,, Giladi A,, Jaitin DA,, Kenigsberg E,, Keren-Shaul H,, Winter D,, Lara-Astiaso D,, Gury M,, Weiner A,, David E,, Cohen N,, Lauridsen FK,, Haas S,, Schlitzer A,, Mildner A,, Ginhoux F,, Jung S,, Trumpp A,, Porse BT,, Tanay A,, Amit I . 2015. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163 : 1663 1677.
21. Nakorn TN,, Miyamoto T,, Weissman IL . 2003. Characterization of mouse clonogenic megakaryocyte progenitors. Proc Natl Acad Sci U S A 100 : 205 210.
22. Terszowski G,, Waskow C,, Conradt P,, Lenze D,, Koenigsmann J,, Carstanjen D,, Horak I,, Rodewald HR . 2005. Prospective isolation and global gene expression analysis of the erythrocyte colony-forming unit (CFU-E). Blood 105 : 1937 1945.
23. Iwasaki H,, Mizuno S,, Mayfield R,, Shigematsu H,, Arinobu Y,, Seed B,, Gurish MF,, Takatsu K,, Akashi K . 2005. Identification of eosinophil lineage-committed progenitors in the murine bone marrow. J Exp Med 201 : 1891 1897.
24. Fogg DK,, Sibon C,, Miled C,, Jung S,, Aucouturier P,, Littman DR,, Cumano A,, Geissmann F . 2006. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311 : 83 87.
25. Traver D,, Akashi K,, Manz M,, Merad M,, Miyamoto T,, Engleman EG,, Weissman IL . 2000. Development of CD8α-positive dendritic cells from a common myeloid progenitor. Science 290 : 2152 2154.
26. Chen CC,, Grimbaldeston MA,, Tsai M,, Weissman IL,, Galli SJ . 2005. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A 102 : 11408 11413.
27. Arinobu Y,, Iwasaki H,, Gurish MF,, Mizuno S,, Shigematsu H,, Ozawa H,, Tenen DG,, Austen KF,, Akashi K . 2005. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci U S A 102 : 18105 18110.
28. Murakami JL,, Xu B,, Franco CB,, Hu X,, Galli SJ,, Weissman IL,, Chen CC . 2016. Evidence that β7 integrin regulates hematopoietic stem cell homing and engraftment through interaction with MAdCAM-1. Stem Cells Dev 25 : 18 26.
29. Pronk CJ,, Rossi DJ,, Månsson R,, Attema JL,, Norddahl GL,, Chan CK,, Sigvardsson M,, Weissman IL,, Bryder D . 2007. Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1 : 428 442.
30. Baum CM,, Weissman IL,, Tsukamoto AS,, Buckle AM,, Peault B . 1992. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A 89 : 2804 2808.
31. Michallet M,, Philip T,, Philip I,, Godinot H,, Sebban C,, Salles G,, Thiebaut A,, Biron P,, Lopez F,, Mazars P,, Roubi N,, Leemhuis T,, Hanania E,, Reading C,, Fine G,, Atkinson K,, Juttner C,, Coiffier B,, Fière D,, Archimbaud E . 2000. Transplantation with selected autologous peripheral blood CD34 +Thy1 + hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution. Exp Hematol 28 : 858 870.
32. Negrin RS,, Atkinson K,, Leemhuis T,, Hanania E,, Juttner C,, Tierney K,, Hu WW,, Johnston LJ,, Shizurn JA,, Stockerl-Goldstein KE,, Blume KG,, Weissman IL,, Bower S,, Baynes R,, Dansey R,, Karanes C,, Peters W,, Klein J . 2000. Transplantation of highly purified CD34 +Thy-1 + hematopoietic stem cells in patients with metastatic breast cancer. Biol Blood Marrow Transplant 6 : 262 271.
33. Muller AM,, Kohrt HE,, Cha S,, Laport G,, Klein J,, Guardino AE,, Johnston LJ,, Stockerl-Goldstein KE,, Hanania E,, Juttner C,, Blume KG,, Negrin RS,, Weissman IL,, Shizuru JA . 2012. Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells. Biol Blood Marrow Transplant 18 : 125 133.
34. Bhatia M,, Wang JC,, Kapp U,, Bonnet D,, Dick JE . 1997. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A 94 : 5320 5325.
35. Uchida N,, Sutton RE,, Friera AM,, He D,, Reitsma MJ,, Chang WC,, Veres G,, Scollay R,, Weissman IL . 1998. HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells. Proc Natl Acad Sci U S A 95 : 11939 11944.
36. Majeti R,, Park CY,, Weissman IL . 2007. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell 1 : 635 645.
37. Galy A,, Travis M,, Cen D,, Chen B . 1995. Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity 3 : 459 473.
38. Manz MG,, Miyamoto T,, Akashi K,, Weissman IL . 2002. Prospective isolation of human clonogenic common myeloid progenitors. Proc Natl Acad Sci U S A 99 : 11872 11877.
39. Edvardsson L,, Dykes J,, Olofsson T . 2006. Isolation and characterization of human myeloid progenitor populations—TpoR as discriminator between common myeloid and megakaryocyte/erythroid progenitors. Exp Hematol 34 : 599 609.
40. Bühring HJ,, Simmons PJ,, Pudney M,, Müller R,, Jarrossay D,, van Agthoven A,, Willheim M,, Brugger W,, Valent P,, Kanz L . 1999. The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multipotent and unipotent progenitors. Blood 94 : 2343 2356.
41. Bühring HJ,, Seiffert M,, Giesert C,, Marxer A,, Kanz L,, Valent P,, Sano K . 2001. The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3. Blood 97 : 3303 3305.
42. Kirshenbaum AS,, Goff JP,, Semere T,, Foster B,, Scott LM,, Metcalfe DD . 1999. Demonstration that human mast cells arise from a progenitor cell population that is CD34 +, c-kit +, and expresses aminopeptidase N (CD13). Blood 94 : 2333 2342.
43. Mori Y,, Iwasaki H,, Kohno K,, Yoshimoto G,, Kikushige Y,, Okeda A,, Uike N,, Niiro H,, Takenaka K,, Nagafuji K,, Miyamoto T,, Harada M,, Takatsu K,, Akashi K . 2009. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. J Exp Med 206 : 183 193.
44. Mori Y,, Chen JY,, Pluvinage JV,, Seita J,, Weissman IL . 2015. Prospective isolation of human erythroid lineage-committed progenitors. Proc Natl Acad Sci U S A 112 : 9638 9643.
45. Li J,, Hale J,, Bhagia P,, Xue F,, Chen L,, Jaffray J,, Yan H,, Lane J,, Gallagher PG,, Mohandas N,, Liu J,, An X . 2014. Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood 124 : 3636 3645.
46. Seita J,, Sahoo D,, Rossi DJ,, Bhattacharya D,, Serwold T,, Inlay MA,, Ehrlich LI,, Fathman JW,, Dill DL,, Weissman IL . 2012. Gene Expression Commons: an open platform for absolute gene expression profiling. PLoS One 7 : e40321. doi:10.1371/journal.pone.0040321.
47. Moore MA,, Metcalf D . 1970. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol 18 : 279 296.
48. Weissman IL,, Baird S,, Gardner RL,, Papaioannou VE,, Raschke W . Normal and neoplastic maturation of T-lineage lymphocytes. Cold Spring Harb Symp Quant Biol 41 : 9 21.
49. Weissman I,, Papaioannou V,, Gardner R . 1978. Fetal hematopoietic origins of the adult hematolymphoid system. Differ Norm Neoplast Hematopoietic Cells 5 : 33 47.
50. Medvinsky A,, Dzierzak E . 1996. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86 : 897 906.
51. Choi K,, Kennedy M,, Kazarov A,, Papadimitriou JC,, Keller G . 1998. A common precursor for hematopoietic and endothelial cells. Development 125 : 725 732.
52. Adamo L,, García-Cardeña G . 2012. The vascular origin of hematopoietic cells. Dev Biol 362 : 1 10.
53. Ueno H,, Weissman IL . 2006. Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev Cell 11 : 519 533.
54. Samokhvalov IM,, Samokhvalova NI,, Nishikawa S . 2007. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446 : 1056 1061.
55. Lux CT,, Yoshimoto M,, McGrath K,, Conway SJ,, Palis J,, Yoder MC . 2008. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood 111 : 3435 3438.
56. Ginhoux F,, Greter M,, Leboeuf M,, Nandi S,, See P,, Gokhan S,, Mehler MF,, Conway SJ,, Ng LG,, Stanley ER,, Samokhvalov IM,, Merad M . 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330 : 841 845.
57. Hoeffel G,, Wang Y,, Greter M,, See P,, Teo P,, Malleret B,, Leboeuf M,, Low D,, Oller G,, Almeida F,, Choy SH,, Grisotto M,, Renia L,, Conway SJ,, Stanley ER,, Chan JK,, Ng LG,, Samokhvalov IM,, Merad M,, Ginhoux F . 2012. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209 : 1167 1181.
58. Gomez Perdiguero E,, Klapproth K,, Schulz C,, Busch K,, Azzoni E,, Crozet L,, Garner H,, Trouillet C,, de Bruijn MF,, Geissmann F,, Rodewald HR . 2015. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518 : 547 551.
59. Sudo K,, Ema H,, Morita Y,, Nakauchi H . 2000. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192 : 1273 1280.
60. Rossi DJ,, Bryder D,, Zahn JM,, Ahlenius H,, Sonu R,, Wagers AJ,, Weissman IL . 2005. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102 : 9194 9199.
61. Pang WW,, Price EA,, Sahoo D,, Beerman I,, Maloney WJ,, Rossi DJ,, Schrier SL,, Weissman IL . 2011. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A 108 : 20012 20017.
62. Beerman I,, Bhattacharya D,, Zandi S,, Sigvardsson M,, Weissman IL,, Bryder D,, Rossi DJ . 2010. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107 : 5465 5470.
63. Challen GA,, Boles NC,, Chambers SM,, Goodell MA . 2010. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell 6 : 265 278.
64. Benz C,, Copley MR,, Kent DG,, Wohrer S,, Cortes A,, Aghaeepour N,, Ma E,, Mader H,, Rowe K,, Day C,, Treloar D,, Brinkman RR,, Eaves CJ . 2012. Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 10 : 273 283.
65. Geiger H,, de Haan G,, Florian MC . 2013. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 13 : 376 389.
66. Chambers SM,, Shaw CA,, Gatza C,, Fisk CJ,, Donehower LA,, Goodell MA . 2007. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5 : e201. doi:10.1371/journal.pbio.0050201.
67. Beerman I,, Rossi DJ . 2014. Epigenetic regulation of hematopoietic stem cell aging. Exp Cell Res 329 : 192 199.
68. Ergen AV,, Boles NC,, Goodell MA . 2012. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119 : 2500 2509.
69. Florian MC,, Dörr K,, Niebel A,, Daria D,, Schrezenmeier H,, Rojewski M,, Filippi MD,, Hasenberg A,, Gunzer M,, Scharffetter-Kochanek K,, Zheng Y,, Geiger H . 2012. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10 : 520 530.
70. Weissman IL . 1996. From thymic lineages back to hematopoietic stem cells, sometimes using homing receptors. J Immunol 156 : 2019 2025.
71. Gambacorti-Passerini C,, le Coutre P,, Mologni L,, Fanelli M,, Bertazzoli C,, Marchesi E,, Di Nicola M,, Biondi A,, Corneo GM,, Belotti D,, Pogliani E,, Lydon NB . 1997. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL + leukemic cells and induces apoptosis. Blood Cells Mol Dis 23 : 380 394.
72. Jamieson CH,, Ailles LE,, Dylla SJ,, Muijtjens M,, Jones C,, Zehnder JL,, Gotlib J,, Li K,, Manz MG,, Keating A,, Sawyers CL,, Weissman IL . 2004. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351 : 657 667.
73. Abrahamsson AE,, Geron I,, Gotlib J,, Dao KH,, Barroga CF,, Newton IG,, Giles FJ,, Durocher J,, Creusot RS,, Karimi M,, Jones C,, Zehnder JL,, Keating A,, Negrin RS,, Weissman IL,, Jamieson CH . 2009. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci U S A 106 : 3925 3929.
74. Weisberg E,, Manley PW,, Cowan-Jacob SW,, Hochhaus A,, Griffin JD . 2007. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7 : 345 356.
75. Hantschel O,, Grebien F,, Superti-Furga G . 2012. The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL. Cancer Res 72 : 4890 4895.
76. Warrell RP Jr,, de Thé H,, Wang ZY,, Degos L . 1993. Acute promyelocytic leukemia. N Engl J Med 329 : 177 189.
77. Pang WW,, Pluvinage JV,, Price EA,, Sridhar K,, Arber DA,, Greenberg PL,, Schrier SL,, Park CY,, Weissman IL . 2013. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci U S A 110 : 3011 3016.
78. Levine RL,, Wadleigh M,, Cools J,, Ebert BL,, Wernig G,, Huntly BJ,, Boggon TJ,, Wlodarska I,, Clark JJ,, Moore S,, Adelsperger J,, Koo S,, Lee JC,, Gabriel S,, Mercher T,, D’Andrea A,, Fröhling S,, Döhner K,, Marynen P,, Vandenberghe P,, Mesa RA,, Tefferi A,, Griffin JD,, Eck MJ,, Sellers WR,, Meyerson M,, Golub TR,, Lee SJ,, Gilliland DG . 2005. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7 : 387 397.
79. Jamieson CH,, Gotlib J,, Durocher JA,, Chao MP,, Mariappan MR,, Lay M,, Jones C,, Zehnder JL,, Lilleberg SL,, Weissman IL . 2006. The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation. Proc Natl Acad Sci U S A 103 : 6224 6229.
80. Verstovsek S,, Passamonti F,, Rambaldi A,, Barosi G,, Rosen PJ,, Rumi E,, Gattoni E,, Pieri L,, Guglielmelli P,, Elena C,, He S,, Contel N,, Mookerjee B,, Sandor V,, Cazzola M,, Kantarjian HM,, Barbui T,, Vannucchi AM . 2014. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 120 : 513 520.
81. Vannucchi AM,, Kiladjian JJ,, Griesshammer M,, Masszi T,, Durrant S,, Passamonti F,, Harrison CN,, Pane F,, Zachee P,, Mesa R,, He S,, Jones MM,, Garrett W,, Li J,, Pirron U,, Habr D,, Verstovsek S . 2015. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372 : 426 435.
82. Oldenborg PA,, Zheleznyak A,, Fang YF,, Lagenaur CF,, Gresham HD,, Lindberg FP . 2000. Role of CD47 as a marker of self on red blood cells. Science 288 : 2051 2054.
83. Adams S,, van der Laan LJ,, Vernon-Wilson E,, Renardel de Lavalette C,, Döpp EA,, Dijkstra CD,, Simmons DL,, van den Berg TK . 1998. Signal-regulatory protein is selectively expressed by myeloid and neuronal cells. J Immunol 161 : 1853 1859.
84. Seiffert M,, Cant C,, Chen Z,, Rappold I,, Brugger W,, Kanz L,, Brown EJ,, Ullrich A,, Bühring HJ . 1999. Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. Blood 94 : 3633 3643.
85. Seiffert M,, Brossart P,, Cant C,, Cella M,, Colonna M,, Brugger W,, Kanz L,, Ullrich A,, Bühring HJ . 2001. Signal-regulatory protein α (SIRPα) but not SIRPβ is involved in T-cell activation, binds to CD47 with high affinity, and is expressed on immature CD34 +CD38 hematopoietic cells. Blood 97 : 2741 2749.
86. Zhao XW,, van Beek EM,, Schornagel K,, Van der Maaden H,, Van Houdt M,, Otten MA,, Finetti P,, Van Egmond M,, Matozaki T,, Kraal G,, Birnbaum D,, van Elsas A,, Kuijpers TW,, Bertucci F,, van den Berg TK . 2011. CD47-signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A 108 : 18342 18347.
87. Ho CC,, Guo N,, Sockolosky JT,, Ring AM,, Weiskopf K,, Özkan E,, Mori Y,, Weissman IL,, Garcia KC . 2015. “Velcro” engineering of high affinity CD47 ectodomain as signal regulatory protein α (SIRPα) antagonists that enhance antibody-dependent cellular phagocytosis. J Biol Chem 290 : 12650 12663.
88. Jaiswal S,, Jamieson CH,, Pang WW,, Park CY,, Chao MP,, Majeti R,, Traver D,, van Rooijen N,, Weissman IL . 2009. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138 : 271 285.
89. Takenaka K,, Prasolava TK,, Wang JC,, Mortin-Toth SM,, Khalouei S,, Gan OI,, Dick JE,, Danska JS . 2007. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat Immunol 8 : 1313 1323.
90. Yamauchi T,, Takenaka K,, Urata S,, Shima T,, Kikushige Y,, Tokuyama T,, Iwamoto C,, Nishihara M,, Iwasaki H,, Miyamoto T,, Honma N,, Nakao M,, Matozaki T,, Akashi K . 2013. Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. Blood 121 : 1316 1325.
91. Kuriyama T,, Takenaka K,, Kohno K,, Yamauchi T,, Daitoku S,, Yoshimoto G,, Kikushige Y,, Kishimoto J,, Abe Y,, Harada N,, Miyamoto T,, Iwasaki H,, Teshima T,, Akashi K . 2012. Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis. Blood 120 : 4058 4067.
92. Majeti R,, Chao MP,, Alizadeh AA,, Pang WW,, Jaiswal S,, Gibbs KD Jr,, van Rooijen N,, Weissman IL . 2009. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138 : 286 299.
93. Liu J,, Wang L,, Zhao F,, Tseng S,, Narayanan C,, Shura L,, Willingham S,, Howard M,, Prohaska S,, Volkmer J,, Chao M,, Weissman IL,, Majeti R . 2015. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One 10 : e0137345. doi:10.1371/journal.pone.0137345.
94. Willingham SB,, Volkmer JP,, Gentles AJ,, Sahoo D,, Dalerba P,, Mitra SS,, Wang J,, Contreras-Trujillo H,, Martin R,, Cohen JD,, Lovelace P,, Scheeren FA,, Chao MP,, Weiskopf K,, Tang C,, Volkmer AK,, Naik TJ,, Storm TA,, Mosley AR,, Edris B,, Schmid SM,, Sun CK,, Chua MS,, Murillo O,, Rajendran P,, Cha AC,, Chin RK,, Kim D,, Adorno M,, Raveh T,, Tseng D,, Jaiswal S,, Enger PO,, Steinberg GK,, Li G,, So SK,, Majeti R,, Harsh GR,, van de Rijn M,, Teng NN,, Sunwoo JB,, Alizadeh AA,, Clarke MF,, Weissman IL . 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109 : 6662 6667.
95. Zhao H,, Wang J,, Kong X,, Li E,, Liu Y,, Du X,, Kang Z,, Tang Y,, Kuang Y,, Yang Z,, Zhou Y,, Wang Q . 2016. CD47 promotes tumor invasion and metastasis in non-small cell lung cancer. Sci Rep 6 : 29719. doi:10.1038/srep29719.
96. Edris B,, Weiskopf K,, Volkmer AK,, Volkmer JP,, Willingham SB,, Contreras-Trujillo H,, Liu J,, Majeti R,, West RB,, Fletcher JA,, Beck AH,, Weissman IL,, van de Rijn M . 2012. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci U S A 109 : 6656 6661.
97. Krampitz GW,, George BM,, Willingham SB,, Volkmer JP,, Weiskopf K,, Jahchan N,, Newman AM,, Sahoo D,, Zemek AJ,, Yanovsky RL,, Nguyen JK,, Schnorr PJ,, Mazur PK,, Sage J,, Longacre TA,, Visser BC,, Poultsides GA,, Norton JA,, Weissman IL . 2016. Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A 113 : 4464 4469.
98. Weiskopf K,, Jahchan NS,, Schnorr PJ,, Cristea S,, Ring AM,, Maute RL,, Volkmer AK,, Volkmer JP,, Liu J,, Lim JS,, Yang D,, Seitz G,, Nguyen T,, Wu D,, Jude K,, Guerston H,, Barkal A,, Trapani F,, George J,, Poirier JT,, Gardner EE,, Miles LA,, de Stanchina E,, Lofgren SM,, Vogel H,, Winslow MM,, Dive C,, Thomas RK,, Rudin CM,, van de Rijn M,, Majeti R,, Garcia KC,, Weissman IL,, Sage J . 2016. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 126 : 2610 2620.
99. Ngo M,, Han A,, Lakatos A,, Sahoo D,, Hachey SJ,, Weiskopf K,, Beck AH,, Weissman IL,, Boiko AD . 2016. Antibody therapy targeting CD47 and CD271 effectively suppresses melanoma metastasis in patient-derived xenografts. Cell Rep 16 : 1701 1716.
100. Liu X,, Pu Y,, Cron K,, Deng L,, Kline J,, Frazier WA,, Xu H,, Peng H,, Fu YX,, Xu MM . 2015. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 21 : 1209 1215.
101. Weiskopf K,, Weissman IL . 2015. Macrophages are critical effectors of antibody therapies for cancer. MAbs 7 : 303 310.
102. Oldenborg PA,, Gresham HD,, Lindberg FP . 2001. CD47-signal regulatory protein α (SIRPα) regulates Fcγ and complement receptor-mediated phagocytosis. J Exp Med 193 : 855 862.
103. Weiskopf K,, Ring AM,, Ho CC,, Volkmer JP,, Levin AM,, Volkmer AK,, Ozkan E,, Fernhoff NB,, van de Rijn M,, Weissman IL,, Garcia KC . 2013. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341 : 88 91.
104. Weiskopf K,, Ring AM,, Schnorr PJ,, Volkmer JP,, Volkmer AK,, Weissman IL,, Garcia KC . 2013. Improving macrophage responses to therapeutic antibodies by molecular engineering of SIRPα variants. Onco Immunology 2 : e25773. doi:10.4161/onci.25773.
105. Chao MP,, Alizadeh AA,, Tang C,, Myklebust JH,, Varghese B,, Gill S,, Jan M,, Cha AC,, Chan CK,, Tan BT,, Park CY,, Zhao F,, Kohrt HE,, Malumbres R,, Briones J,, Gascoyne RD,, Lossos IS,, Levy R,, Weissman IL,, Majeti R . 2010. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142 : 699 713.
106. Tseng D,, Volkmer JP,, Willingham SB,, Contreras-Trujillo H,, Fathman JW,, Fernhoff NB,, Seita J,, Inlay MA,, Weiskopf K,, Miyanishi M,, Weissman IL . 2013. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A 110 : 11103 11108.
107. Barclay AN,, Van den Berg TK . 2014. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 32 : 25 50.
108. Soto-Pantoja DR,, Kaur S,, Roberts DD . 2015. CD47 signaling pathways controlling cellular differentiation and responses to stress. Crit Rev Biochem Mol Biol 50 : 212 230.
109. Mateo V,, Brown EJ,, Biron G,, Rubio M,, Fischer A,, Deist FL,, Sarfati M . 2002. Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization. Blood 100 : 2882 2890.
110. Kikuchi Y,, Uno S,, Kinoshita Y,, Yoshimura Y,, Iida S,, Wakahara Y,, Tsuchiya M,, Yamada-Okabe H,, Fukushima N . 2005. Apoptosis inducing bivalent single-chain antibody fragments against CD47 showed antitumor potency for multiple myeloma. Leuk Res 29 : 445 450.
111. Manna PP,, Frazier WA . 2004. CD47 mediates killing of breast tumor cells via Gi-dependent inhibition of protein kinase A. Cancer Res 64 : 1026 1036.
112. Reinhold MI,, Lindberg FP,, Kersh GJ,, Allen PM,, Brown EJ . 1997. Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway. J Exp Med 185 : 1 11.
113. Soto-Pantoja DR,, Terabe M,, Ghosh A,, Ridnour LA,, DeGraff WG,, Wink DA,, Berzofsky JA,, Roberts DD . 2014. CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. Cancer Res 74 : 6771 6783.
114. Lagasse E,, Weissman IL . 1994. bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. J Exp Med 179 : 1047 1052.
115. Feng M,, Chen JY,, Weissman-Tsukamoto R,, Volkmer JP,, Ho PY,, McKenna KM,, Cheshier S,, Zhang M,, Guo N,, Gip P,, Mitra SS,, Weissman IL . 2015. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci U S A 112 : 2145 2150.
116. Chao MP,, Jaiswal S,, Weissman-Tsukamoto R,, Alizadeh AA,, Gentles AJ,, Volkmer J,, Weiskopf K,, Willingham SB,, Raveh T,, Park CY,, Majeti R,, Weissman IL . 2010. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2 : 63ra94. doi:10.1126/scitranslmed.3001375.
117. Seita J,, Weissman IL . 2010. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2 : 640 653.

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