osteoprotegerin and Blast-Crisis

Acute lymphoblastic leukemia (ALL) dissemination to the central nervous system (CNS) is a challenging clinical problem whose underlying mechanisms are poorly understood. Here, we show that primary human ALL samples injected into the femora of immunodeficient mice migrate to the skull and vertebral bone marrow and provoke bone lesions that enable passage into the subarachnoid space. Treatment of leukemia xenografted mice with a biologic antagonist of receptor activator of nuclear factor κB ligand (RANKL) blocks this entry route. In addition to erosion of cranial and vertebral bone, samples from individuals with B-ALL also penetrate the blood-cerebrospinal fluid barrier of recipient mice. Co-administration of C-X-C chemokine receptor 4 (CXCR4) and RANKL antagonists attenuate both identified routes of entry. Our findings suggest that targeted RANKL and CXCR4 pathway inhibitors could attenuate routes of leukemia blast CNS invasion and provide benefit for B-ALL-affected individuals.

Topics: Animals; Blast Crisis; Cell Line, Tumor; Central Nervous System; Fusion Proteins, bcr-abl; Gene Rearrangement; Histone-Lysine N-Methyltransferase; Humans; Mice, Inbred NOD; Models, Biological; Myeloid-Lymphoid Leukemia Protein; Neoplasm Invasiveness; Osteoprotegerin; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; RANK Ligand; Receptors, CXCR4; Spine; Subarachnoid Space; Xenograft Model Antitumor Assays

We came across a rare case of acute megakaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interleukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient.

Topics: Adult; Blast Crisis; Glycoproteins; Humans; Interleukin-11; Leukemia, Megakaryoblastic, Acute; Male; Osteoprotegerin; Osteosclerosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Cells, Cultured; Up-Regulation