Integrins and the Metastasis-like Dissemination of Acute Lymphoblastic Leukemia to the Central Nervous System

Abstract

Acute lymphoblastic leukemia (ALL) disseminates with high prevalence to the central nervous system (CNS) in a process resembling aspects of the CNS surveillance of normal immune cells as well as aspects of brain metastasis from solid cancers. Importantly, inside the CNS, the ALL blasts are typically confined within the cerebrospinal fluid (CSF)-filled cavities of the subarachnoid space, which they use as a sanctuary protected from both chemotherapy and immune cells. At present, high cumulative doses of intrathecal chemotherapy are administered to patients, but this is associated with neurotoxicity and CNS relapse still occurs. Thus, it is imperative to identify markers and novel therapy targets specific to CNS ALL. Integrins represent a family of adhesion molecules involved in cell-cell and cell-matrix interactions, implicated in the adhesion and migration of metastatic cancer cells, normal immune cells, and leukemic blasts. The ability of integrins to also facilitate cell-adhesion mediated drug resistance, combined with recent discoveries of integrin-dependent routes of leukemic cells into the CNS, have sparked a renewed interest in integrins as markers and therapeutic targets in CNS leukemia. Here, we review the roles of integrins in CNS surveillance by normal lymphocytes, dissemination to the CNS by ALL cells, and brain metastasis from solid cancers. Furthermore, we discuss whether ALL dissemination to the CNS abides by known hallmarks of metastasis, and the potential roles of integrins in this context.

Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology

“…Because most chemotherapeutic medications are unable to cross the blood-brain barrier (BBB), leukemic cells buried in the CNS are unable to be efficiently removed and hence become the source of recurrent extramedullary leukemia [ 94 , 115 , 116 ]. Blocking CXCR4, the receptor for the chemoattractant CXCL12, only partially inhibits acute lymphoblastic leukemia cell invasion of human cerebrospinal fluid.…”

Flow Sorting, Whole Genome Amplification and Next-Generation Sequencing as Combined Tools to Study Heterogeneous Acute Lymphoblastic Leukemia

“…The preservation of the IG/TR gene rearrangements is found in only 70% of BCP-ALL and 90% of T-ALL patients at the time of relapse [6,7], either because of continuing V(D)J recombinase activity in the malignant cells, or due to the limited sensitivity of the available methods for identifying IG/TR genes that cause minor subpopulations to be overlooked at the time of diagnosis. Of note, the metastasis-like dissemination of ALL cells to the central nervous system is a common cause of relapse in ALL [8], and in some patients, the IG gene rearrangements that dominantly present in the ALL cells in the CNS are found only at very low levels in the bone marrow at the time of diagnosis [9]. Improving the sensitivity of the IG/TR gene rearrangement analysis at the time of diagnosis could advance the detection of minimal residual disease over the course of treatment and improve the prediction of relapse in patients with heterogenous leukemia.…”