Leukaemia hijacks a neural mechanism to invade the central nervous system

Abstract

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

“…CXCR4-CXCL12 has been implicated as a potential pathway that drives T-ALL infiltration into the CNS. (22)(23)(24)(25) By deleting the CXCR4 gene from T-ALL, we confirm previous findings that demonstrate prolonged survival in vivo with decreased overall and neurologic clinical scores. (22,23) Thus, in the setting of CXCR4 inhibition, T-ALL CNS infiltration would be blocked and potentially ruxolitinib and venetoclax may be able to clear systemic disease.…”

Leukaemia follows a blood-vessel track to enter the nervous system

“…■ Frank Winkler is in the Department of Neurology, University Hospital Heidelberg, and is also at the German Cancer Research Center, 69120 Heidelberg, Germany. e-mail: frank.winkler@med.uni-heidelberg.de 1 report that human bloodcancer cells in mice reach the central nervous system by migrating along the external surface of blood vessels. This solves the mystery of how these cells leave their site of origin in the bone marrow and reach a region called the subarachnoid space, which contains cerebrospinal fluid.…”

“…If moreeffective and lesstoxic approaches became available to prevent disease spread to the CNS, this might benefit many people with ALL. On page 55, Yao et al 1 report a hitherto unknown route that ALL cells use to enter the CNS, and suggest a possible therapeutic approach that is worth investigating.…”

Identification of an Integrin α6‐Targeted Peptide for Nasopharyngeal Carcinoma‐Specific Nanotherapeutics

“…[3] The integrin α6 subunit combines with either integrin β1 or β4 subunit to form integrin α6β1 or α6β4 heterodimer, respectively. [17] The abnormally high expression of integrin α6β1 and α6β4 contributes to cancer initiation, [15] angiogenesis, [18] invasion, [19] and metastasis. [17] The abnormally high expression of integrin α6β1 and α6β4 contributes to cancer initiation, [15] angiogenesis, [18] invasion, [19] and metastasis.…”