title: The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts.
abstract: Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.
authors: Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom;
authors: Mark T S
authors: MT
authors: Williams
authors: Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan;
authors: Yasar M
authors: http://orcid.org/0000-0002-3479-6153
authors: YM
authors: Yousafzai
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Alex
authors: A
authors: Elder
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Paediatric and Adolescent Haematology and Oncology, Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom;
authors: Klaus
authors: K
authors: Rehe
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Paediatric and Adolescent Haematology and Oncology, Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom;
authors: Simon
authors: http://orcid.org/0000-0001-9163-5738
authors: S
authors: Bomken
authors: Functional Genomics and Childhood Leukemia Research Center, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel;
authors: Liron
authors: L
authors: Frishman-Levy
authors: Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel;
authors: Sigal
authors: S
authors: Tavor
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Paul
authors: P
authors: Sinclair
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Katie
authors: K
authors: Dormon
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Dino
authors: D
authors: Masic
authors: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom;
authors: Tracey
authors: T
authors: Perry
authors: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom;
authors: Victoria J
authors: VJ
authors: Weston
authors: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom;
authors: Pamela
authors: P
authors: Kearns
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Helen
authors: H
authors: Blair
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Lisa J
authors: LJ
authors: Russell
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Olaf
authors: O
authors: Heidenreich
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors: Julie A E
authors: JA
authors: Irving
authors: Functional Genomics and Childhood Leukemia Research Center, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel;
authors: Shai
authors: S
authors: Izraeli
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Paediatric and Adolescent Haematology and Oncology, Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom;
authors: Josef
authors: J
authors: Vormoor
authors: Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom;
authors: Gerard J
authors: GJ
authors: Graham
authors: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and Department of Paediatric Haematology, Royal Hospital for Children, Glasgow, United Kingdom.
authors: Christina
authors: http://orcid.org/0000-0001-5449-5246
authors: C
authors: Halsey
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D016543:Central Nervous System Neoplasms / Q000134:cerebrospinal fluid / Q000556:secondary; D006801:Humans; D017254:Leukemic Infiltration / Q000473:pathology*; D007962:Leukocytes / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D012008:Recurrence; D014183:Transplantation, Heterologous