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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
The prognostic and therapeutic potential of HO-1 in leukemia and MDS
Cell Communication and Signaling Open Access 13 March 2023
The prognostic role of C-KIT, TET1 and TET2 gene expression in Acute Myeloid Leukemia
Molecular Biology Reports Open Access 12 November 2022
Role of Long Intergenic Noncoding RNAs in Cancers with an Overview of MicroRNA Binding
Molecular Diagnosis & Therapy Open Access 26 October 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).
Miles, L. A. et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 587, 477–482 (2020).
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).
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).
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).
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).
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).
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).
Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005).
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).
Barcos, M. et al. An autopsy study of 1206 acute and chronic leukemias (1958 to 1982). Cancer 60, 827–837 (1987).
Viadana, E., Bross, I. D. & Pickren, J. W. An autopsy study of the metastatic patterns of human leukemias. Oncology 35, 87–96 (1978).
Döhner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129, 424–447 (2017).
Inaba, H., Greaves, M. & Mullighan, C. G. Acute lymphoblastic leukaemia. Lancet 381, 1943–1955 (2013).
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).
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).
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).
Gokbuget, N. & Hoelzer, D. Meningeosis leukaemica in adult acute lymphoblastic leukaemia. J. Neurooncol. 38, 167–180 (1998).
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).
Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).
Zhang, Y., Gao, S., Xia, J. & Liu, F. Hematopoietic hierarchy – an updated roadmap. Trends Cell Biol. 28, 976–986 (2018).
Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320 (2019).
Morita, K. et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat. Commun. 11, 5327 (2020).
Zhang, B. et al. Heterogeneity of leukemia-initiating capacity of chronic myelogenous leukemia stem cells. J. Clin. Invest. 126, 975–991 (2016).
Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).
Visvader, J. E. & Lindeman, G. J. Cancer stem cells: current status and evolving complexities. Stem Cell 10, 717–728 (2012).
Ye, H. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 19, 23–37 (2016).
Holyoake, T. L. & Vetrie, D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood 129, 1595–1606 (2017).
Thomas, D. & Majeti, R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 129, 1577–1585 (2017).
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).
Ferrando, A. A. & López-Otín, C. Clonal evolution in leukemia. Nat. Med. 23, 1135–1145 (2017).
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).
Puente, X. S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).
Nervi, B. et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 113, 6206–6214 (2009).
Boyerinas, B. et al. Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy. Blood 121, 4821–4831 (2013).
Crane, G. M., Jeffery, E. & Morrison, S. J. Adult haematopoietic stem cell niches. Nat. Rev. Immunol. 17, 573–590 (2017).
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).
Maloney, D. G., Smith, B. & Rose, A. Rituximab: mechanism of action and resistance. Semin. Oncol. 29, 2–9 (2002).
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).
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).
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).
McEver, R. P. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc. Res. 107, 331–339 (2015).
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).
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).
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).
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).
Natoni, A., Macauley, M. S. & O’Dwyer, M. E. Targeting selectins and their ligands in cancer. Front. Oncol. 6, 1–12 (2016).
Chien, S. S. et al. E-selectin ligand expression by leukemic blasts is associated with prognosis in patients with AML. Blood 132, 1513 (2018).
Stucki, A. et al. Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination. Blood 97, 2121–2129 (2001).
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).
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).
Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).
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).
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).
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).
Yao, H. et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature 560, 55–60 (2018).
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).
Shanafelt, T. D. et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N. Engl. J. Med. 381, 432–443 (2019).
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).
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).
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).
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).
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).
Fiegl, M. et al. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood 113, 1504–1512 (2009).
Fei, F. et al. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia 24, 813–820 (2010).
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).
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).
Buonamici, S. et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000–1004 (2009).
Ma, S. et al. Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen. J. Hematol. Oncol. 7, 71 (2014).
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).
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).
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).
Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).
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).
Hussong, J. W., Rodgers, G. M. & Shami, P. J. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 95, 309–313 (2000).
Nombela-Arrieta, C. & Manz, M. G. Quantification and three-dimensional microanatomical organization of the bone marrow. Blood Adv. 1, 407–416 (2017).
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).
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).
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).
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).
Ridley, A. J. Life at the leading edge. Cell 145, 1012–1022 (2011).
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).
Rochelle, T. et al. p210-bcr-abl induces amoeboid motility by recruiting ADF/destrin through RhoA/ROCK1. FASEB J. 27, 123–134 (2013).
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).
Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).
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).
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).
Cougoule, C. et al. Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis. Blood 115, 1444–1452 (2010).
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).
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).
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).
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).
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).
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).
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).
Navarro, S. M. et al. Musculoskeletal imaging findings of hematologic malignancies. RadioGraphics 37, 881–900 (2017).
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).
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).
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).
Passaro, D. et al. CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia. Cancer Cell 27, 769–779 (2015).
Pitt, L. A. et al. CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell 27, 755–768 (2015).
Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).
Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).
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).
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).
McDonald, B. & Kubes, P. Interactions between CD44 and hyaluronan in leukocyte trafficking. Front. Immunol. 6, 68 (2015).
Gutjahr, J. C., Greil, R. & Hartmann, T. N. The role of CD44 in the pathophysiology of chronic lymphocytic leukemia. Front. Immunol. 6, 177 (2015).
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).
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).
Bajaj, J. et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 30, 792–805 (2016).
Méndez-Ferrer, S. et al. Bone marrow niches in haematological malignancies. Nat. Rev. Cancer 20, 285–298 (2020).
Jacamo, R. et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood 123, 2691–2702 (2014).
Dias, S. et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J. Clin. Invest. 106, 511–521 (2000).
Fiedler, W. et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood 89, 1870–1875 (1997).
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).
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).
Witkowski, M. T. et al. Extensive remodeling of the immune microenvironment in B cell acute lymphoblastic leukemia. Cancer Cell 37, 867–882.e812 (2020).
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).
Ebinger, S. et al. Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia. Cancer Cell 30, 849–862 (2016).
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).
Cahu, X. et al. Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia. Blood Adv. 1, 1760–1772 (2017).
Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).
Colmone, A. et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322, 1861–1865 (2008).
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).
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).
Zhang, B. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21, 577–592 (2012).
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).
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).
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).
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).
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).
Schmidt, T. & Carmeliet, P. Angiogenesis: a target in solid tumors, also in leukemia? Hematol. Am. Soc. Hematol Educ. Program. 2011, 1–8 (2011).
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).
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).
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).
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).
Padro, T. et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 8, 2637–2644 (2000).
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).
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).
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).
Barbier, V. et al. Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance. Nat. Commun. 11, 2042 (2020).
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).
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).
Lam, K. Y. & Tang, V. Metastatic tumors to the spleen: a 25-year clinicopathologic study. Arch. Pathol. Lab. Med. 124, 526–530 (2000).
Juarez, J. et al. CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 21, 1249–1257 (2007).
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).
Gutjahr, J. C. et al. Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia. Blood 131, 1337–1349 (2018).
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).
Marom, A. et al. CD84 mediates CLL-microenvironment interactions. Oncogene 36, 628–638 (2017).
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).
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).
Habermann, T. M. & Steensma, D. P. Lymphadenopathy. Mayo Clin. Proc. 75, 723–732 (2000).
Libman, H. Generalized lymphadenopathy. J. Gen. Intern. Med. 2, 48–58 (1987).
Ruddle, N. H. High endothelial venules and lymphatic vessels in tertiary lymphoid organs: characteristics, functions, and regulation. Front. Immunol. 7, 491 (2016).
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).
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).
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).
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).
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).
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).
Kipps, T. J. et al. Chronic lymphocytic leukaemia. Nat. Rev. Dis. Prim. 3, 16096 (2017).
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).
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).
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).
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).
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).
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).
Price, R. A. & Johnson, W. W. The central nervous system in childhood leukemia: I. The arachnoid. Cancer 31, 520–533 (1973).
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).
Nayar, G. et al. Leptomeningeal disease: current diagnostic and therapeutic strategies. Oncotarget 8, 73312–73328 (2017).
Mastorakos, P. & McGavern, D. The anatomy and immunology of vasculature in the central nervous system. Sci. Immunol. 4, eaav0492 (2019).
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).
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).
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).
Munch, V. et al. Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor. Blood 130, 643–654 (2017).
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).
Ramirez, M. et al. Chemokines in leukemic infiltration of the central nervous system in childhood acute lymphoblastic leukemia. Blood 114, 651 (2009).
Alsadeq, A. et al. The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system. Haematologica 102, 346–355 (2017).
Marz, M. et al. Pediatric acute lymphoblastic leukemia — conquering the CNS across the choroid plexus. Leuk. Res. 71, 47–54 (2018).
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).
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).
Frishman-Levy, L. et al. Central nervous system acute lymphoblastic leukemia: role of natural killer cells. Blood 125, 3420–3431 (2015).
Jonart, L. M. et al. Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance. Haematologica 105, 2130–2140 (2020).
Gaynes, J. S. et al. The central nervous system microenvironment influences the leukemia transcriptome and enhances leukemia chemo-resistance. Haematologica 102, 136–139 (2017).
Barnhill, R. L. et al. Atypical spitzoid melanocytic neoplasms with angiotropism: a potential mechanism of locoregional involvement. Am. J. Dermatopathol. 33, 236–243 (2011).
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).
Miyashiro, D. & Sanches, J. A. Cutaneous manifestations of adult T-cell leukemia/lymphoma. Semin. Diagnostic Pathol. 37, 81–91 (2020).
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).
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).
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).
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).
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).
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).
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).
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).
Liesveld, J. L. et al. Effects of AMD3100 on transmigration and survival of acute myelogenous leukemia cells. Leuk. Res. 31, 1553–1563 (2007).
Tavor, S. et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia 22, 2151–5158 (2008).
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).
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).
Greenbaum, A. M. & Link, D. C. Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization. Leukemia 25, 211–217 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04571645 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04704323 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04240704 (2021).
Yoshie, O. & Matsushima, K. CCR4 and its ligands: from bench to bedside. Int. Immunol. 27, 11–20 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04185220 (2019).
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).
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).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03616470 (2009).
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).
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).
US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04197999 (2019).
Hsieh, Y. T. et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 121, 1814–1818 (2013).
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).
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).
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).
Gang, E. J. et al. Integrin α6 mediates drug resistance of acute lymphoblastic B-cell leukemia. Blood 136, 210–223 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04803123 (2021).
Dobosz, P. & Dzieciątkowski, T. The intriguing history of cancer immunotherapy. Front. Immunol. 10, 2965 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01838395 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02763384 (2016).
Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).
Jabbour, E. et al. Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies. Cancer 116, 2290–2300 (2010).
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).
Santos, F. P. & O’Brien, S. Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease? Cancer J. 18, 396–403 (2012).
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).
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).
Lad, D. et al. CLL: common leukemia; uncommon presentations. Indian J. Hematol. Blood Transfus. 32, 268–275 (2016).
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).
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).
Dong, M. & Blobe, G. C. Role of transforming growth factor-β in hematologic malignancies. Blood 107, 4589–4596 (2006).
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).
Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016).
Yan, Y. et al. Antileukemia activity of a natural killer cell line against human leukemias. Clin. Cancer Res. 4, 2859–2868 (1998).
Swerdlow, S. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Medicine) 4th Edn, Vol. 2 (World Health Organization 2017).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Shulman, Z. et al. Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin. Immunity 30, 384–396 (2008).
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).
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).
Charras, G. & Sahai, E. Physical influences of the extracellular environment on cell migration. Nat. Rev. Mol. Cell Biol. 15, 813–824 (2014).
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).
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).
Schoumacher, M., Louvard, D. & Vignjevic, D. Cytoskeleton networks in basement membrane transmigration. Eur. J. Cell Biol. 90, 93–99 (2011).
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).
Linder, S. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 17, 107–117 (2007).
Krause, M. & Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat. Rev. Mol. Cell Biol. 15, 577–590 (2014).
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.
The authors have received research funding from Bayer Pharmaceutical and Glycomimetics, Inc.
Peer review information
Nature Reviews Cancer thanks D. Bonnet and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Choroid plexus
A secretory tissue in the brain that produces cerebrospinal fluid.
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.
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.
Rights and permissions
About this article
Cite this article
Whiteley, A.E., Price, T.T., Cantelli, G. et al. Leukaemia: a model metastatic disease. Nat Rev Cancer 21, 461–475 (2021). https://doi.org/10.1038/s41568-021-00355-z
This article is cited by
The prognostic and therapeutic potential of HO-1 in leukemia and MDS
Cell Communication and Signaling (2023)
Role of Long Intergenic Noncoding RNAs in Cancers with an Overview of MicroRNA Binding
Molecular Diagnosis & Therapy (2023)
The prognostic role of C-KIT, TET1 and TET2 gene expression in Acute Myeloid Leukemia
Molecular Biology Reports (2023)
Osteoarticular manifestation of acute lymphoblastic leukemia in adults: a literature review
Clinical Rheumatology (2023)
Green synthesis of bimetallic ZnO–CuO nanoparticles and their cytotoxicity properties
Scientific Reports (2021)