Routes and molecular mechanisms of central nervous system involvement in acute myeloid leukemia (Review)

Abstract

Acute myeloid leukemia (AML) is a predominant form of leukemia. Central nervous system (CNS) involvement complicates its diagnosis due to limited diagnostic tools, as well as its treatment due to inadequate therapeutic methodologies and poor prognosis. Furthermore, its incidence rate is unclear. The mechanisms of AML cell mobilization from the bone marrow (BM) to the CNS are not fully elucidated, and the molecular factors contributing to CNS infiltration are insufficiently recognized. The present review aimed to enhance the understanding of CNS involvement of AML and its impact on CNS. The latest research on the pathways and mechanisms facilitating AML cells to escape the BM and infiltrate the CNS was reviewed. Additionally, novel therapeutic strategies targeting specific molecules and genes for treating CNS involvement in AML were examined.

Keywords: AML; CNS; brain barrier; cell adhesion molecules; therapeutic strategies.

Figure 1.

Anatomical structures of sinusoids. (A) Blood supply in the bone marrow. (B) Sinusoid's location. (C and D) The marrow-blood barriers of patients with AML and healthy individuals. The adventitial cell cover rate is reduced in patients with AML. AML, acute myeloid leukemia.

Figure 2.

Escape mechanisms of AML cells. This figure illustrates two distinct processes: On the left side of the dotted lines-a mechanism underlying the capture of the AML cells within the sinusoid. On the right side of the dotted lines-a mechanism facilitating the transportation of AML cells into circulation. AML, acute myeloid leukemia; ECM, extracellular matrix; CD38, cluster of differentiation 38; CD49d, the rate-limiting α-chain of the CD49d/CD29 integrin heterodimer very late antigen-4; VCAM-1, vascular cell-adhesion molecule 1; MMP-9, matrix metalloproteinase-9; CD31, cluster of differentiation 31; LFA-1, lymphocyte function associated antigen-1; ICAM-1, intercellular cell adhesion molecule-1; SDF-1, stromal cell-derived factor 1; CXCR-4, chemokine receptor 4.

Figure 3.

Routes and anatomical structures potentially involved in infiltration of the CNS. Green arrow: Routes of acute myeloid leukemia cell infiltration into the CNS. Orange arrow: Direction of the CSF influx. Route 1: Through the blood-brain barrier (1). Route 2: Through the blood-leptomeningeal barrier (2). Route 3: Through the blood-CSF barrier (3). Route 4: Through the bridging veins (4). Route 5: Through the dural lymphatic vessels (5). CNS, central nervous system; CSF, cerebrospinal fluid.

Figure 4.

Mechanisms of the central nervous system exploited by AML cells. AML, acute myeloid leukemia; APOE-POPC, liposome-reconstituted APOE protein; LILRB4, immunoglobulin-like receptor B4; D3Amut, genetic mutation in exon 18 of DNMT3A; TWIST1, TWIST1 gene; TIMP-2, TIMP-2 gene; IRF7, interferon regulatory factor 7; TGIF-1, TG-interacting factor 1; CD56, cluster of differentiation 56. MMPs, matrix metalloproteinases; CD49d, rate-limiting α-chain of the CD49d/CD29 integrin heterodimer very late antigen-4; VCAM-1, vascular cell-adhesion molecule 1; LFA-1, lymphocyte function-associated antigen-1; ICAM-1, intercellular cell adhesion molecule-1.