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Leukaemia: a model metastatic disease

Abstract

In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells uniquely possess the innate ability for migration and invasion. Dedifferentiated, malignant leukocytes retain the benign leukocytes’ capacity for cell motility and survival in the circulation, while acquiring the potential for rapid and uncontrolled cell division. For these reasons, leukaemias, although not traditionally considered as metastatic diseases, are in fact models of highly efficient metastatic spread. Accordingly, they are often aggressive and challenging diseases to treat. In this Perspective, we discuss the key molecular processes that facilitate metastasis in a variety of leukaemic subtypes, the clinical significance of leukaemic invasion into specific tissues and the current pipeline of treatments targeting leukaemia metastasis.

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Fig. 1: Primary metastatic profiles of leukaemia metastasis.
Fig. 2: The leukaemia bone marrow microenvironment.
Fig. 3: The leukaemia splenic microenvironment.
Fig. 4: Routes of leukaemia central nervous system invasion.

References

  1. 1.

    Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Miles, L. A. et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587, 477–482 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Vetrie, D., Helgason, G. V. & Copland, M. The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML. Nat. Rev. Cancer 20, 158–173 (2020).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12, 1167–1174 (2006).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Krause, D. S., Lazarides, K., Lewis, J. B., Von Andrian, U. H. & Van Etten, R. A. Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood 123, 1361–1371 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Krause, D. S., Lazarides, K., von Andrian, U. H. & Van Etten, R. A. Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells. Nat. Med. 12, 1175–1180 (2006).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Lafouresse, F. et al. L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo. Blood 126, 1336–1345 (2015).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Messinger, Y., Chelstrom, L., Gunther, R. & Uckun, F. M. Selective homing of human leukemic B-cell precursors to specific lymphohematopoietic microenvironments in SCID mice: a role for the beta 1 integrin family surface adhesion molecules VLA-4 and VLA-5. Leuk. Lymphoma 23, 61–69 (1996).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Tavor, S. et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID Mice. Cancer Res. 64, 2817–2824 (2004).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Barcos, M. et al. An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer 60, 827–837 (1987).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Viadana, E., Bross, I. D. & Pickren, J. W. An autopsy study of the metastatic patterns of human leukemias. Oncology 35, 87–96 (1978).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Döhner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129, 424–447 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Inaba, H., Greaves, M. & Mullighan, C. G. Acute lymphoblastic leukaemia. Lancet 381, 1943–1955 (2013).

    PubMed  Article  Google Scholar 

  15. 15.

    Arber, D. A. et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127, 2391–2405 (2016).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Gharbaran, R., Park, J., Kim, C., Goy, A. & Suh, K. S. Circulating tumor cells in Hodgkin’s lymphoma — a review of the spread of HL tumor cells or their putative precursors by lymphatic and hematogenous means, and their prognostic significance. Crit. Rev. Oncol. Hematol. 89, 404–417 (2014).

    PubMed  Article  Google Scholar 

  17. 17.

    Granell, M. et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica 102, 1099–1104 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Gokbuget, N. & Hoelzer, D. Meningeosis leukaemica in adult acute lymphoblastic leukaemia. J. Neurooncol. 38, 167–180 (1998).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Cancela, C. S., Murao, M., Viana, M. B. & de Oliveira, B. M. Incidence and risk factors for central nervous system relapse in children and adolescents with acute lymphoblastic leukemia. Rev. Bras. Hematol. Hemoter. 34, 436–441 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Zhang, Y., Gao, S., Xia, J. & Liu, F. Hematopoietic hierarchy – an updated roadmap. Trends Cell Biol. 28, 976–986 (2018).

    PubMed  Article  Google Scholar 

  22. 22.

    Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Morita, K. et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat. Commun. 11, 5327 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Zhang, B. et al. Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells. J. Clin. Invest. 126, 975–991 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Visvader, J. E. & Lindeman, G. J. Cancer stem cells: current status and evolving complexities. Stem Cell 10, 717–728 (2012).

    CAS  Google Scholar 

  27. 27.

    Ye, H. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 19, 23–37 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    de Haas, V. et al. Quantification of minimal residual disease in children with oligoclonal B-precursor acute lymphoblastic leukemia indicates that the clones that grow out during relapse already have the slowest rate of reduction during induction therapy. Leukemia 15, 134–140 (2001).

    PubMed  Article  Google Scholar 

  31. 31.

    Ferrando, A. A. & López-Otín, C. Clonal evolution in leukemia. Nat. Med. 23, 1135–1145 (2017).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Li, A.-H., Rosenquist, R., Forestier, E., Lindh, J. & Roos, G. Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection. Leukemia Res. 25, 1033–1045 (2001).

    CAS  Article  Google Scholar 

  33. 33.

    Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).

    CAS  Article  Google Scholar 

  34. 34.

    Nervi, B. et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 113, 6206–6214 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Boyerinas, B. et al. Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy. Blood 121, 4821–4831 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Crane, G. M., Jeffery, E. & Morrison, S. J. Adult haematopoietic stem cell niches. Nat. Rev. Immunol. 17, 573–590 (2017).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Ghielmini, M. et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 103, 4416–4423 (2004).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Maloney, D. G., Smith, B. & Rose, A. Rituximab: mechanism of action and resistance. Semin. Oncol. 29, 2–9 (2002).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Gökbuget, N. et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood 120, 1868–1876 (2012).

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Kamps, W. A. et al. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988–1991). Blood 94, 1226–1236 (1999).

    CAS  PubMed  Google Scholar 

  41. 41.

    Miniero, R. et al. Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: a 10-year follow-up study. Italian Association of Pediatric Hematology-Oncology (AIEOP). Med. Pediatr. Oncol. 24, 71–76 (1995).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    McEver, R. P. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc. Res. 107, 331–339 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Spertini, C. et al. Acute myeloid and lymphoblastic leukemia cell interactions with endothelial selectins: critical role of PSGL-1, CD44 and CD43. Cancers (Basel) 11, 1253 (2019).

    CAS  Article  Google Scholar 

  44. 44.

    Myung, J. H. et al. Direct measurements on CD24-mediated rolling of human breast cancer MCF-7 cells on E-selectin. Anal. Chem. 83, 1078–1083 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Renkonen, J., Paavonen, T. & Renkonen, R. Endothelial and epithelial expression of sialyl Lewisx and sialyl Lewisa in lesions of breast carcinoma. Int. J. Cancer 74, 296–300 (1997).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Shirure, V. S., Henson, K. A., Schnaar, R. L., Nimrichter, L. & Burdick, M. M. Gangliosides expressed on breast cancer cells are E-selectin ligands. Biochem. Biophys. Res. Commun. 406, 423–429 (2011).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Natoni, A., Macauley, M. S. & O’Dwyer, M. E. Targeting selectins and their ligands in cancer. Front. Oncol. 6, 1–12 (2016).

    Article  Google Scholar 

  48. 48.

    Chien, S. S. et al. E-selectin ligand expression by leukemic blasts is associated with prognosis in patients with AML. Blood 132, 1513 (2018).

    Article  Google Scholar 

  49. 49.

    Stucki, A. et al. Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination. Blood 97, 2121–2129 (2001).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Dagdemir, A., Ertem, U., Duru, F. & Kirazli, S. Soluble L-selectin increases in the cerebrospinal fluid prior to meningeal involvement in children with acute lymphoblastic leukemia. Leuk. Lymphoma 28, 391–398 (1998).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Spertini, O. et al. High levels of the shed form of L-selectin are present in patients with acute leukemia and inhibit blast cell adhesion to activated endothelium. Blood 84, 1249–1256 (1994).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Blenc, A. M., Chiagev, A., Sklar, L. & Larson, R. S. VLA-4 affinity correlates with peripheral blood white cell count and DNA content in patients with precursor B-ALL. Leukemia 17, 641–643 (2003).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Filshie, R., Gottlieb, D. & Bradstock, K. VLA-4 is involved in the engraftment of the human pre-B acute lymphoblastic leukaemia cell line NALM-6 in SCID mice. Br. J. Haematol. 102, 1292–1300 (1998).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Hu, Z. & Slayton, W. B. Integrin VLA-5 and FAK are good targets to improve treatment response in the philadelphia chromosome positive acute lymphoblastic leukemia. Front. Oncol. 4, 1–10 (2014).

    Article  Google Scholar 

  56. 56.

    Yao, H. et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 560, 55–60 (2018).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Tissino, E. et al. Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. J. Exp. Med. 215, 681–697 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Shanafelt, T. D. et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N. Engl. J. Med. 381, 432–443 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Konoplev, S. et al. Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutatedFLT3 acute myeloid leukemia with normal karyotype. Cancer 109, 1152–1156 (2007).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    van den Berk, L. C. J. et al. Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia. Br. J. Haematol. 166, 240–249 (2014).

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Crazzolara, R. et al. High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br. J. Haematol. 115, 545–553 (2001).

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    De Lourdes Perim, A., Amarante, M. K., Guembarovski, R. L., De Oliveira, C. E. C. & Watanabe, M. A. E. CXCL12/CXCR4 axis in the pathogenesis of acute lymphoblastic leukemia (ALL): a possible therapeutic target. Cell Mol. Life Sci. 72, 1715–1723 (2015).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Jin, L. et al. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Mol. Cancer Therapeutics 7, 48–58 (2008).

    CAS  Article  Google Scholar 

  64. 64.

    Fiegl, M. et al. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood 113, 1504–1512 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Fei, F. et al. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia 24, 813–820 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Sison, E. A. R., McIntyre, E., Magoon, D. & Brown, P. Dynamic chemotherapy-induced upregulation of CXCR4 expression: a mechanism of therapeutic resistance in pediatric AML. Mol. Cancer Res. 11, 1004–1016 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Burger, J. A. Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): from understanding the basics towards therapeutic targeting. Semin. Cancer Biol. 20, 424–430 (2010).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Buonamici, S. et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000–1004 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Ma, S. et al. Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen. J. Hematol. Oncol. 7, 71 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Till, K. J., Lin, K., Zuzel, M. & Cawley, J. C. The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes. Blood 99, 2977–2984 (2002).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Faaij, C. M. J. M. et al. Chemokine/chemokine receptor interactions in extramedullary leukaemia of the skin in childhood AML: differential roles for CCR2, CCR5, CXCR4 and CXCR7. Pediatric Blood Cancer 55, 344–348 (2010).

    PubMed  Article  Google Scholar 

  72. 72.

    Ishida, T. et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin. Cancer Res. 9, 3625–3634 (2003).

    CAS  PubMed  Google Scholar 

  73. 73.

    Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Perez-Atayde, A. R. et al. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am. J. Pathol. 150, 815–821 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Hussong, J. W., Rodgers, G. M. & Shami, P. J. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 95, 309–313 (2000).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Nombela-Arrieta, C. & Manz, M. G. Quantification and three-dimensional microanatomical organization of the bone marrow. Blood Adv. 1, 407–416 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Van Der Velde-Zimmermann, D. et al. Fibronectin distribution in human bone marrow stroma: matrix assembly and tumor cell adhesion via α5β1 integrin. Exp. Cell Res. 230, 111–120 (1997).

    PubMed  Article  Google Scholar 

  78. 78.

    Reilly, J., Nash, J., Mackie, M. & McVerry, B. Distribution of laminin and fibronectin in normal and pathological lymphoid tissue. J. Clin. Pathol. 38, 849–854 (1985).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Voermans, C., van Heese, W. P. M., de Jong, I., Gerritsen, W. R. & van der Schoot, C. E. Migratory behavior of leukemic cells from acute myeloid leukemia patients. Leukemia 16, 650–657 (2002).

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Matsunaga, T. et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat. Med. 9, 1158–1165 (2003).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Ridley, A. J. Life at the leading edge. Cell 145, 1012–1022 (2011).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Daubon, T. et al. Differential motility of p190bcr-abl- and p210 bcr-abl-expressing cells: respective roles of Vav and Bcr-Abl GEFs. Oncogene 27, 2673–2685 (2008).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Rochelle, T. et al. p210-bcr-abl induces amoeboid motility by recruiting ADF/destrin through RhoA/ROCK1. FASEB J. 27, 123–134 (2013).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Velázquez-Avila, M. et al. High cortactin expression in B-cell acute lymphoblastic leukemia is associated with increased transendothelial migration and bone marrow relapse. Leukemia 33, 1337–1348 (2019).

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Pankova, K., Rosel, D., Novotny, M. & Brabek, J. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell Mol. Life Sci. 67, 63–71 (2010).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Daubon, T., Rochelle, T., Bourmeyster, N. & Génot, E. Invadopodia and rolling-type motility are specific features of highly invasive p190bcr-abl leukemic cells. Eur. J. Cell Biol. 91, 978–987 (2012).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Cougoule, C. et al. Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis. Blood 115, 1444–1452 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Poincloux, R., Cougoule, C., Daubon, T., Maridonneau-Parini, I. & Le Cabec, V. Tyrosine-phosphorylated STAT5 accumulates on podosomes in Hck-transformed fibroblasts and chronic myeloid leukemia cells. J. Cell. Physiol. 213, 212–220 (2007).

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Redondo-Muñoz, J. et al. MMP-9 in B-cell chronic lymphocytic leukemia is up-regulated by α4β1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration. Blood 108, 3143–3151 (2006).

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Kamiguti, A. S. et al. The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia. Br. J. Haematol. 125, 128–140 (2004).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Sawicki, G., Matsuzaki, A. & Janowska-Wieczorek, A. Expression of the active form of MMP-2 on the surface of leukemic cells accounts for their in vitro invasion. J. Cancer Res. Clin. Oncol. 124, 245–252 (1998).

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Spiegel, A. et al. Unique SDF-1 – induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood 103, 2900–2907 (2004).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Masuda, M. et al. CADM1 interacts with Tiam1 and promotes invasive phenotype of human T-cell leukemia virus type I-transformed cells and adult T-cell leukemia cells. J. Biol. Chem. 285, 15511–15522 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Cárcamo, C. et al. Galectin-8 binds specific β1 integrins and induces polarized spreading highlighted by asymmetric lamellipodia in Jurkat T cells. Exp. Cell Res. 312, 374–386 (2006).

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Navarro, S. M. et al. Musculoskeletal imaging findings of hematologic malignancies. RadioGraphics 37, 881–900 (2017).

    PubMed  Article  Google Scholar 

  97. 97.

    Detterbeck, F. C. et al. The IASLC lung cancer staging project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J. Thorac. Oncol. 5, 651–665 (2016).

    Article  Google Scholar 

  98. 98.

    Lapidot, T. & Kollet, O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 16, 1992–2003 (2002).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Menu, E. et al. The involvement of stromal derived factor 1alpha in homing and progression of multiple myeloma in the 5TMM model. Haematologica 91, 605–612 (2006).

    CAS  PubMed  Google Scholar 

  100. 100.

    Passaro, D. et al. CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia. Cancer Cell 27, 769–779 (2015).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Pitt, L. A. et al. CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell 27, 755–768 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Wicklein, D. et al. E- and P-selectins are essential for repopulation of chronic myelogenous and chronic eosinophilic leukemias in a scid mouse xenograft model. PLoS ONE 8, e70139 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Sackstein, R. et al. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat. Med. 14, 181–187 (2008).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    McDonald, B. & Kubes, P. Interactions between CD44 and hyaluronan in leukocyte trafficking. Front. Immunol. 6, 68 (2015).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Gutjahr, J. C., Greil, R. & Hartmann, T. N. The role of CD44 in the pathophysiology of chronic lymphocytic leukemia. Front. Immunol. 6, 177 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Chen, C., Zhao, S., Karnad, A. & Freeman, J. W. The biology and role of CD44 in cancer progression: therapeutic implications. J. Hematol. Oncol. 11, 64 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. 109.

    Senbanjo, L. T. & Chellaiah, M. A. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front. Cell Dev. Biol. 5, 18 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Bajaj, J. et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 30, 792–805 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Méndez-Ferrer, S. et al. Bone marrow niches in haematological malignancies. Nat. Rev. Cancer 20, 285–298 (2020).

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Jacamo, R. et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood 123, 2691–2702 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Dias, S. et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J. Clin. Invest. 106, 511–521 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Fiedler, W. et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood 89, 1870–1875 (1997).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Liersch, R. et al. Expression of VEGF-C and its receptor VEGFR-3 in the bone marrow of patients with acute myeloid leukaemia. Leuk. Res. 32, 954–961 (2008).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Padró, T. et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 16, 1302–1310 (2002).

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    Witkowski, M. T. et al. Extensive remodeling of the immune microenvironment in B cell acute lymphoblastic leukemia. Cancer Cell 37, 867–882.e812 (2020).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Ishikawa, F. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat. Biotechnol. 25, 1315–1321 (2007).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Ebinger, S. et al. Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia. Cancer Cell 30, 849–862 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Stier, S. et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201, 1781–1791 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Cahu, X. et al. Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia. Blood Adv. 1, 1760–1772 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Colmone, A. et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322, 1861–1865 (2008).

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Carey, A. 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. 18, 3204–3218 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Welner, R. S. et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell 27, 671–681 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Zhang, B. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21, 577–592 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Hanoun, M. et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15, 365–375 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Duarte, D., Hawkins, E. D., Akinduro, O., Purton, L. E. & Carlin, L. M. Inhibition of endosteal vascular niche remodeling article inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Stem Cell 22, 64–77.e66 (2018).

    CAS  Google Scholar 

  129. 129.

    Passaro, D. et al. Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid. Cancer Cell 32, 324–341 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Kebelmann-Betzing, C. et al. Characterization of cytokine, growth factor receptor, costimulatory and adhesion molecule expression patterns of bone marrow blasts in relapsed childhood B cell precursor all. Cytokine 13, 39–50 (2001).

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Hou, H. A. et al. Expression of angiopoietins and vascular endothelial growth factors and their clinical significance in acute myeloid leukemia. Leuk. Res. 32, 904–912 (2008).

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Schmidt, T. & Carmeliet, P. Angiogenesis: a target in solid tumors, also in leukemia? Hematol. Am. Soc. Hematol Educ. Program. 2011, 1–8 (2011).

    Article  Google Scholar 

  133. 133.

    Norén-Nyström, U. et al. Vascular density in childhood acute lymphoblastic leukaemia correlates to biological factors and outcome. Br. J. Haematol. 146, 521–530 (2009).

    PubMed  Article  Google Scholar 

  134. 134.

    Aguayo, A. et al. Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer 95, 1923–1930 (2002).

    PubMed  Article  Google Scholar 

  135. 135.

    De Bont, E. S. J. M., Rosati, S., Jacobs, S., Kamps, W. A. & Vellenga, E. Increased bone marrow vascularization in patients with acute myeloid leukaemia: a possible role for vascular endothelial growth factor. Br. J. Haematol. 113, 296–304 (2001).

    PubMed  Article  Google Scholar 

  136. 136.

    Hiramatsu, A. et al. Disease-specific expression of VEGF and its receptors in AML cells: possible autocrine pathway of VEGF/type1 receptor of VEGF in t(15;17) AML and VEGF/type2 receptor of VEGF in t(8;21) AML. Leuk. Lymphoma 47, 89–95 (2006).

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Padro, T. et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 8, 2637–2644 (2000).

    Article  Google Scholar 

  138. 138.

    Santos, S. C. R. & Dias, S. Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood 103, 3883–3889 (2004).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Favreau, A. J., Vary, C. P. H., Brooks, P. C. & Sathyanarayana, P. Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia. Cancer Med. 3, 265–272 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Verma, D. et al. Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia. Leukemia 34, 1540–1552 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Barbier, V. et al. Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance. Nat. Commun. 11, 2042 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Krenn, P. W., Koschmieder, S. & Fässler, R. Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches. Proc. Natl Acad. Sci. USA 117, 24326 (2020).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Tavor, S. et al. Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD / SCID chimeric mice. Blood 106, 2120–2127 (2005).

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Lam, K. Y. & Tang, V. Metastatic tumors to the spleen: a 25-year clinicopathologic study. Arch. Pathol. Lab. Med. 124, 526–530 (2000).

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Juarez, J. et al. CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 21, 1249–1257 (2007).

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Yang, F. et al. Monocyte-derived leukemia-associated macrophages facilitate extramedullary distribution of T-cell acute lymphoblastic leukemia cells. Cancer Res. 80, 3677–3691 (2020).

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Gutjahr, J. C. et al. Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia. Blood 131, 1337–1349 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Gatjen, M. et al. Splenic marginal zone granulocytes acquire an accentuated neutrophil B-cell helper phenotype in chronic lymphocytic leukemia. Cancer Res. 76, 5253–5265 (2016).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Marom, A. et al. CD84 mediates CLL-microenvironment interactions. Oncogene 36, 628–638 (2017).

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Saulep-Easton, D. et al. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia 30, 163–172 (2016).

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    Pereira, E. R., Jones, D., Jung, K. & Padera, T. P. The lymph node microenvironment and its role in the progression of metastatic cancer. Semin. Cell Dev. Biol. 38, 98–105 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Habermann, T. M. & Steensma, D. P. Lymphadenopathy. Mayo Clin. Proc. 75, 723–732 (2000).

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Libman, H. Generalized lymphadenopathy. J. Gen. Intern. Med. 2, 48–58 (1987).

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Ruddle, N. H. High endothelial venules and lymphatic vessels in tertiary lymphoid organs: characteristics, functions, and regulation. Front. Immunol. 7, 491 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. 155.

    Fecteau, J. F. & Kipps, T. J. Structure and function of the hematopoietic cancer niche: focus on chronic lymphocytic leukemia. Front. Biosci. 4 S, 61–73 (2012).

    Article  Google Scholar 

  156. 156.

    Calpe, E. et al. ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation. Blood 118, 4401–4410 (2011).

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Gunn, M. D. et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl Acad. Sci. USA 95, 258–263 (1998).

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Alfonso-Pérez, M. et al. Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia. J. Leukoc. Biol. 79, 1157–1165 (2006).

    PubMed  Article  CAS  Google Scholar 

  159. 159.

    Cuesta, C., Munoz-Callega, C., Loscertales, J., Terron, F. & Mol, W. CAP-100: first-in-class antibody for CCR7+ hematological malignancies. J. Clin. Oncol. 37, e19008 (2019).

    Article  Google Scholar 

  160. 160.

    Redondo-Muñoz, J. et al. a4Β1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood 112, 169–178 (2008).

    PubMed  Article  CAS  Google Scholar 

  161. 161.

    Kipps, T. J. et al. Chronic lymphocytic leukaemia. Nat. Rev. Dis. Prim. 3, 16096 (2017).

    PubMed  Article  Google Scholar 

  162. 162.

    Burger, J. A. et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood 113, 3050–3058 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Hartmann, E. M., Rudelius, M., Burger, J. A. & Rosenwald, A. CCL3 chemokine expression by chronic lymphocytic leukemia cells orchestrates the composition of the microenvironment in lymph node infiltrates. Leuk. Lymphoma 57, 563–571 (2016).

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Burger, J. A. et al. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96, 2655–2663 (2000).

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Burger, M. et al. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 106, 1824–1830 (2005).

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Nishio, M. et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. Blood 106, 1012–1020 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Tsukada, N., Burger, J. A., Zvaifler, N. J. & Kipps, T. J. Distinctive features of “nurselike” cells that differentiate in the context of chronic lymphocytic leukemia. Blood 99, 1030–1037 (2002).

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Price, R. A. & Johnson, W. W. The central nervous system in childhood leukemia: I. The arachnoid. Cancer 31, 520–533 (1973).

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Brower, J. V., Saha, S., Rosenberg, S. A., Hullett, C. R. & Ian Robins, H. Management of leptomeningeal metastases: Prognostic factors and associated outcomes. J. Clin. Neurosci. 27, 130–137 (2016).

    PubMed  Article  Google Scholar 

  170. 170.

    Nayar, G. et al. Leptomeningeal disease: current diagnostic and therapeutic strategies. Oncotarget 8, 73312–73328 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Mastorakos, P. & McGavern, D. The anatomy and immunology of vasculature in the central nervous system. Sci. Immunol. 4, eaav0492 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. 172.

    Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Williams, M. T. et al. The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood 127, 1998–2006 (2016).

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Bartram, J. et al. High throughput sequencing in acute lymphoblastic leukemia reveals clonal architecture of central nervous system and bone marrow compartments. Haematologica 103, 110–114 (2018).

    Article  CAS  Google Scholar 

  175. 175.

    Munch, V. et al. Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor. Blood 130, 643–654 (2017).

    PubMed  Article  CAS  Google Scholar 

  176. 176.

    Kinjyo, I., Bragin, D., Grattan, R., Winter, S. S. & Wilson, B. S. Leukemia-derived exosomes and cytokines pave the way for entry into the brain. J. Leukoc. Biol. 105, 741–753 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Ramirez, M. et al. Chemokines in leukemic infiltration of the central nervous system in childhood acute lymphoblastic leukemia. Blood 114, 651 (2009).

    Google Scholar 

  178. 178.

    Alsadeq, A. et al. The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system. Haematologica 102, 346–355 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Marz, M. et al. Pediatric acute lymphoblastic leukemia — conquering the CNS across the choroid plexus. Leuk. Res. 71, 47–54 (2018).

    PubMed  Article  Google Scholar 

  180. 180.

    Naumann, J. A. & Gordon, P. M. In vitro model of leukemia cell migration across the blood–cerebrospinal fluid barrier. Leuk. Lymphoma 58, 1747–1749 (2017).

    PubMed  Article  Google Scholar 

  181. 181.

    Scharff, B. F. S. S. et al. A comprehensive clinical study of integrins in acute lymphoblastic leukemia indicates a role of alpha 6/CD49f in persistent minimal residual disease and alpha 5 in the colonization of cerebrospinal fluid. Leuk. Lymphoma 7, 1714–1718 (2020).

    Article  CAS  Google Scholar 

  182. 182.

    Frishman-Levy, L. et al. Central nervous system acute lymphoblastic leukemia: role of natural killer cells. Blood 125, 3420–3431 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Jonart, L. M. et al. Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance. Haematologica 105, 2130–2140 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Gaynes, J. S. et al. The central nervous system microenvironment influences the leukemia transcriptome and enhances leukemia chemo-resistance. Haematologica 102, 136–139 (2017).

    Article  CAS  Google Scholar 

  185. 185.

    Barnhill, R. L. et al. Atypical spitzoid melanocytic neoplasms with angiotropism: a potential mechanism of locoregional involvement. Am. J. Dermatopathol. 33, 236–243 (2011).

    PubMed  Article  Google Scholar 

  186. 186.

    Wong, C., Helm, M., Kalb, R., Helm, T. & Zeitouni, N. The presentation, pathology, and current management strategies of cutaneous metastasis. North. Am. J. Med. Sci. 5, 499–504 (2013).

    Article  Google Scholar 

  187. 187.

    Miyashiro, D. & Sanches, J. A. Cutaneous manifestations of adult T-cell leukemia/lymphoma. Semin. Diagnostic Pathol. 37, 81–91 (2020).

    Article  Google Scholar 

  188. 188.

    Berg, E. L. et al. The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule-1. J. Exp. Med. 174, 1461–1466 (1991).

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Campbell, J. J., O’Connell, D. J. & Wurbel, M.-A. Cutting edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions. J. Immunol. 178, 3358 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. 190.

    Mohle, R. et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br. J. Haematol. 110, 563–572 (2000).

    CAS  PubMed  Article  Google Scholar 

  191. 191.

    Schlesinger, M. & Bendas, G. Contribution of very late antigen-4 (VLA-4) integrin to cancer progression and metastasis. Cancer Metastasis Rev. 34, 575–591 (2015).

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    DiPersio, J. F. et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J. Clin. Oncol. 27, 4767–4773 (2009).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    DiPersio, J. F. et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 113, 5720–5726 (2009).

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Zeng, Z. et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 113, 6215–6224 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. 195.

    Welschinger, R. et al. Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice. Exp. Hematol. 41, 293–302.e291 (2013).

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Liesveld, J. L. et al. Effects of AMD3100 on transmigration and survival of acute myelogenous leukemia cells. Leuk. Res. 31, 1553–1563 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Tavor, S. et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia 22, 2151–5158 (2008).

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Uy, G. L. et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 119, 3917–3924 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Uy, G. L. et al. A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia. Blood Cancer J. 7, 2–5 (2017).

    Article  Google Scholar 

  200. 200.

    Greenbaum, A. M. & Link, D. C. Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization. Leukemia 25, 211–217 (2011).

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Petit, I., Ponomaryov, T., Zipori, D. & Tsvee, L. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat. Immunol. 3, 687–694 (2002).

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Löwenberg, B. et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N. Engl. J. Med. 349, 743–752 (2003).

    PubMed  Article  Google Scholar 

  203. 203.

    Pabst, T. et al. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine. Blood 119, 5367–5373 (2012).

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Dombret, H. et al. A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. N. Engl. J. Med. 332, 1678–1683 (1995).

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    G, H. et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 90, 4710–4718 (1997).

    Article  Google Scholar 

  206. 206.

    Huselton, E. et al. Updated study results of CX-01, an inhibitor of CXCL12/CXCR4, and azacitidine for the treatment of hypomethylating agent refractory AML and MDS. Blood 134, 3915 (2019).

    Article  Google Scholar 

  207. 207.

    Pillozzi, S. et al. Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow-induced chemoresistance in acute leukemias. Oncol. Rep. 41, 312–324 (2019).

    CAS  PubMed  Google Scholar 

  208. 208.

    Kovacsovics, T. et al. A randomized phase II trial of CX-01 with standard therapy in elderly patients with acute myeloid leukemia (AML). J. Clin. Oncol. 37, 7001 (2019).

    Article  Google Scholar 

  209. 209.

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04571645 (2020).

  210. 210.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04704323 (2021).

  211. 211.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04240704 (2021).

  212. 212.

    Yoshie, O. & Matsushima, K. CCR4 and its ligands: from bench to bedside. Int. Immunol. 27, 11–20 (2015).

    CAS  PubMed  Article  Google Scholar 

  213. 213.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04185220 (2019).

  214. 214.

    DeAngelo, D. J. et al. Uproleselan (GMI-1271), an E-selectin antagonist, improves the efficacy and safety of chemotherapy in relapsed/refractory (R/R) and newly diagnosed older patients with acute myeloid leukemia: final, correlative, and subgroup analyses. Blood 132, 331 (2018).

    Article  Google Scholar 

  215. 215.

    Zhang, W. et al. Dual E-selectin/CXCR4 antagonist GMI-1359 exerts efficient anti-leukemia effects in a FLT3 ITD mutated acute myeloid leukemia patient-derived xenograft murine model. Blood 128, 3519 (2016).

    Article  Google Scholar 

  216. 216.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03616470 (2009).

  217. 217.

    Godavarthy, P. S. et al. The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis. Haematologica 105, 136–147 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Price, T. T. et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci. Transl Med. 8, 340ra373 (2016).

    Article  Google Scholar 

  219. 219.

    US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04197999 (2019).

  220. 220.

    Hsieh, Y. T. et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 121, 1814–1818 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    Hamidi, H., Pietilä, M. & Ivaska, J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer 115, 1017–1023 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Herman, S. E. M. et al. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin. Cancer Res. 21, 4642–4651 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  223. 223.

    DiGiuseppe, J. A., Fuller, S. G. S. G. & Borowitz, M. J. Overexpression of CD49f in precursor B-cell acute lymphoblastic leukemia: Potential usefulness in minimal residual disease detection. Cytometry B Clin. Cytometry 76B, 150–155 (2009).

    Article  Google Scholar 

  224. 224.

    Gang, E. J. et al. Integrin α6 mediates drug resistance of acute lymphoblastic B-cell leukemia. Blood 136, 210–223 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  225. 225.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04803123 (2021).

  226. 226.

    Dobosz, P. & Dzieciątkowski, T. The intriguing history of cancer immunotherapy. Front. Immunol. 10, 2965 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. 227.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01838395 (2013).

  228. 228.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02763384 (2016).

  229. 229.

    Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  230. 230.

    Jabbour, E. et al. Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies. Cancer 116, 2290–2300 (2010).

    CAS  PubMed  Article  Google Scholar 

  231. 231.

    Ten Hacken, E. & Burger, J. A. Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment. Biochim. Biophys. Acta 1863, 401–413 (2016).

    PubMed  Article  CAS  Google Scholar 

  232. 232.

    Santos, F. P. & O’Brien, S. Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease? Cancer J. 18, 396–403 (2012).

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Tees, M. T. & Flinn, I. W. Chronic lymphocytic leukemia and small lymphocytic lymphoma: two faces of the same disease. Expert Rev Hematol. 10, 137–146 (2017).

    CAS  PubMed  Article  Google Scholar 

  234. 234.

    McKenna, M. K. et al. Splenic microenvironment is important in the survival and growth of chronic lymphocytic leukemia in mice. J. Immunol. 198 (Suppl. 1), 130-20 (2017).

    Google Scholar 

  235. 235.

    Lad, D. et al. CLL: common leukemia; uncommon presentations. Indian J. Hematol. Blood Transfus. 32, 268–275 (2016).

    PubMed  Article  Google Scholar 

  236. 236.

    Altintas, A., Cil, T., Kilinc, I., Kaplan, M. A. & Ayyildiz, O. Central nervous system blastic crisis in chronic myeloid leukemia on imatinib mesylate therapy: a case report. J. Neurooncol. 84, 103–105 (2007).

    PubMed  Article  Google Scholar 

  237. 237.

    Rajappa, S., Uppin, S. G., Raghunadharao, D., Rao, I. S. & Surath, A. Isolated central nervous system blast crisis in chronic myeloid leukemia. Hematol. Oncol. 22, 179–181 (2004).

    PubMed  Article  Google Scholar 

  238. 238.

    Dong, M. & Blobe, G. C. Role of transforming growth factor-β in hematologic malignancies. Blood 107, 4589–4596 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  239. 239.

    Bauvois, B., Dumont, J., Mathiot, C. & Kolb, J. P. Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons. Leukemia 16, 791–798 (2002).

    CAS  PubMed  Article  Google Scholar 

  240. 240.

    Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  241. 241.

    Yan, Y. et al. Antileukemia activity of a natural killer cell line against human leukemias. Clin. Cancer Res. 4, 2859–2868 (1998).

    CAS  PubMed  Google Scholar 

  242. 242.

    Swerdlow, S. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Medicine) 4th Edn, Vol. 2 (World Health Organization 2017).

  243. 243.

    Lampert, I. A., Hegde, U. & Van Noorden, S. The splenic white pulp in chronic lymphocytic leukaemia: a microenvironment associated with CR2 (CD21) expression, cell transformation and proliferation. Leuk. Lymphoma 1, 319–326 (1990).

    CAS  PubMed  Article  Google Scholar 

  244. 244.

    Somers, W. S., Tang, J., Shaw, G. D. & Camphausen, R. T. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe X and PSGL-1. Cell 103, 467–479 (2000).

    CAS  PubMed  Article  Google Scholar 

  245. 245.

    Alon, R. et al. α4β1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the α4-cytoplasmic domain. J. Cell Biol. 171, 1073–1084 (1995).

    Article  CAS  Google Scholar 

  246. 246.

    Kuwano, Y., Spelten, O., Zhang, H., Ley, K. & Zarbock, A. Rolling on E- or P-selectin induces the extended but not high-affinity conformation of LFA-1 in neutrophils. Blood 116, 617–624 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  247. 247.

    Shamri, R. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat. Immunol. 6, 497–506 (2005).

    CAS  PubMed  Article  Google Scholar 

  248. 248.

    Zarbock, A., Ley, K. & McEver, R. P. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 118, 6743–6751 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Alon, R. & Shulman, Z. Chemokine triggered integrin activation and actin remodeling events guiding lymphocyte migration across vascular barriers. Exp. Cell Res. 317, 632–641 (2010).

    Article  CAS  Google Scholar 

  250. 250.

    Barreiro, O. et al. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J. Cell Biol. 157, 1233–1245 (1998).

    Article  Google Scholar 

  251. 251.

    Phillipson, M. et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J. Exp. Med. 203, 2569–2575 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  252. 252.

    Shulman, Z. et al. Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin. Immunity 30, 384–396 (2008).

    Article  CAS  Google Scholar 

  253. 253.

    Nourshargh, S., Hordijk, P. L. & Sixt, M. Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nat. Rev. Mol. Cell Biol. 11, 366–378 (2010).

    CAS  PubMed  Article  Google Scholar 

  254. 254.

    Carman, C. V. & Springer, T. A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377–388 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  255. 255.

    Charras, G. & Sahai, E. Physical influences of the extracellular environment on cell migration. Nat. Rev. Mol. Cell Biol. 15, 813–824 (2014).

    CAS  PubMed  Article  Google Scholar 

  256. 256.

    Bovellan, M., Fritzsche, M., Stevens, C. & Charras, G. Death-associated protein kinase (DAPK) and signal transduction: blebbing in programmed cell death. FEBS J. 277, 58–65 (2010).

    CAS  PubMed  Article  Google Scholar 

  257. 257.

    Buccione, R., Caldieri, G. & Ayala, I. Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev. 28, 137–149 (2009).

    PubMed  Article  Google Scholar 

  258. 258.

    Schoumacher, M., Louvard, D. & Vignjevic, D. Cytoskeleton networks in basement membrane transmigration. Eur. J. Cell Biol. 90, 93–99 (2011).

    CAS  PubMed  Article  Google Scholar 

  259. 259.

    Poincioux, R., Lizárraga, F. & Chavrier, P. Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia. J. Cell Sci. 122, 3015–3024 (2009).

    Article  CAS  Google Scholar 

  260. 260.

    Linder, S. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 17, 107–117 (2007).

    CAS  PubMed  Article  Google Scholar 

  261. 261.

    Krause, M. & Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat. Rev. Mol. Cell Biol. 15, 577–590 (2014).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The authors thank A. Chenn and P. Islam for their discussions and careful review of the manuscript. The authors apologize to all colleagues whose work could not be discussed owing to space limitations.

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All authors researched data for the article, substantially contributed to discussion of the content, and wrote sections of the article. A.E.W., T.T.P. and D.A.S. reviewed and edited the article before submission. A.E.W. and D.A.S. designed the figures.

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Correspondence to Dorothy A. Sipkins.

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The authors have received research funding from Bayer Pharmaceutical and Glycomimetics, Inc.

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Glossary

Choroid plexus

A secretory tissue in the brain that produces cerebrospinal fluid.

Diapedesis

The process of extravasating out of a vessel into the surrounding stroma.

Endosteal niche

The niche in the bone marrow adjacent to the bone lining (endosteum).

Germinal centre

Site within the spleen and lymph node where B cells proliferate and differentiate.

High endothelial venules

(HEVs). Specialized post-capillary venules in the lymph node that allow for the trafficking of immune cells in and out of this lymphoid organ.

Intravital microscopy

High-resolution imaging of a living organism to study biological events at the cellular level.

Leptomeninges

The inner two meningeal layers that surround the brain and spinal cord and contain cerebrospinal fluid.

Minimal residual disease

(MRD). A subclinical amount of disease remaining after therapy that can fuel relapse.

Nurse-like cells

Monocyte-derived cells that support the survival and growth of chronic lymphocytic leukaemia.

Sinusoidal vessels

Large vessels found in the bone marrow, spleen, lymph node and liver that contain fenestrations allowing the trafficking of cells across the vascular endothelium.

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Whiteley, A.E., Price, T.T., Cantelli, G. et al. Leukaemia: a model metastatic disease. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00355-z

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