AN EXPERIMENTAL-MODEL OF HUMAN LEUKEMIC MENINGITIS IN THE NUDE RAT

An experimental animal model of meningeal leukemia was developed in th e nude rat, rnu/rnu, using the human-derived acute lymphoblastic leuke mia cell line HPB-ALL. Anesthetized rats were placed in a modified ste reotaxic frame and then injected intrathecally, at the level of the ci sterna magna, with human leukemic cells. Cerebrospinal fluid and tissu e samples from brain, spinal cord, heart, liver, kidney, spleen, bone marrow, and cervical lymph nodes were subjected to histopathologic exa mination and molecular genetic screening by clonotype primer-directed polymerase chain reaction (CPD-PCR). Ninety-three percent of animals ( n = 14) developed signs of meningeal irritation leading to death 30 to 63 days postinjection (median, 36.0 days, mean, 38.7); death occurred between 30 and 39 days in 77% of all animals. Leukemic cells progress ively infiltrated the pericerebellar and pericerebral subarachnoid spa ce and infiltrated the Virchow-Robin (perivascular) space. The infiltr ating meningeal leukemia closely resembled the pathologic presentation in the human condition, By CPD-PCR, leukemic cells were first detecte d in cerebrospinal fluid (CSF) on day 4 postinjection, were variably p resent over the ensuing 17 days, and were consistently detected after day 21. At terminal stages, CPD-PCR tissue surveys showed leukemic DNA in all brains and spinal cords and rarely in cervical lymph nodes, bu t leukemic DNA was not detected in any other tissue screened. Leukemic meningitis was reliably produced with a predictable survival time. In trathecal administration of leukemic cells was an efficient means of t ransmitting leukemic meningitis and it compartmentalized the disease t o the central nervous system (CNS), eliminating potential complication s of systemic illness, The use of human-derived cell lines may render this model more relevant to the development of future therapeutic stra tegies to treat leukemia and lymphoma that invade the CNS. (C) 1997 by The American Society of Hematology.