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| Status |
Public on Jul 12, 2018 |
| Title |
Leukemia hijacks a neural mechanism to invade the central nervous system |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Acute lymphoblastic leukemia (ALL) has a striking propensity to metastasize to the central nervous system (CNS).1 In contrast to solid tumor brain metastases, ALL seldom involves the parenchyma but is isolated to the leptomeninges, an infrequent site for carcinomatous invasion.2,3 While CNS metastasis is characteristic across ALL subtypes, a unifying mechanism for invasion has not been determined. Here we show that ALL cells in circulation are unable to breach the blood brain barrier; instead they migrate into the CNS along vessels that passage directly between vertebral or calvarial bone marrow (BM) and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, known to coordinate neuronal progenitor cell pathfinding in the CNS.4-6 The laminin receptor a6 integrin is expressed by most ALL.7,8 We found that a6/laminin mediated ALL migration toward cerebrospinal fluid (CSF) in vitro. ALL-xenografted mice treated with either a PI3Kd inhibitor that decreased ALL a6 expression or specific a6 neutralizing antibodies showed significantly less ALL transit along bridging vessels, CSF blast counts and CNS disease symptoms despite minimally decreased BM disease burden. Our data suggest that a6 integrin expression, common in ALL, allows cells to coopt neural migratory pathways to invade the CNS.
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| Overall design |
NALM6 ALL cells isolated from the bone marrow (BM) or the cerebrospinal fluid (CSF) of SCID mice treated with control (n=6 mice) or PI3Kd (n=6 mice for BM isolation, n=4mice for CNS isolation).
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| Contributor(s) |
Yao H, T Price T |
| Citation(s) |
30022166 |
| Submission date |
May 18, 2018 |
| Last update date |
Oct 16, 2018 |
| Contact name |
Dorothy Sipkins |
| Organization name |
Duke University
|
| Department |
Hematological Malignancies and Cell Therapy
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| Lab |
Sipkins Lab
|
| Street address |
905S La Salle Street
|
| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27710 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL23126 |
[Clariom_D_Human] Affymetrix Human Clariom D Assay [transcript (gene) version] |
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| Samples (22)
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| Relations |
| BioProject |
PRJNA471996 |
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