Analysis of the molecular mechanism underlying bone marrow necrosis with acute lymphoblastic leukemia

Bone marrow necrosis (BMN) is a rare phenomenon in children with malignancies, occurring most commonly in patients with acute lymphoblastic leukemia (ALL). The pathophysiology of this phenomenon has not been identified. We analyzed seven BMN cases with ALL in order to elucidate the underlying mechanism. Serum high-mobility group box 1 (HMGB1), cytochrome C, cytokines, and chemokines were measured, and real-time quantitative reverse transcription-polymerase chain reaction (RQ-RT-PCR) and immunochemistry of death-related molecules were analyzed using bone marrow samples. The serum levels of 17 of 27 cytokines and chemokines were found to be significantly elevated in patients with BMN in comparison to those in healthy volunteers; however, IFN-γ and IL-10 were not elevated. The cytokine pattern was different to that reported in hemophagocytic lymphohistiocytosis. The HMGB1 and cytochrome C levels in patients with BMN were not elevated. RQ-RT-PCR revealed significant overexpression of Fas-ligand, perforin, and granzyme B in the bone marrow of patients with ALL complicated with BMN compared with that in healthy volunteers and in patients with ALL without BMN. On immunohistochemistry, we identified leukemic cell-eliciting Fas-ligand and macrophage-eliciting TNF-α. Thus, no close relationship with massive necrosis or the intrinsic pathway of apoptosis was identified in the occurrence of BMN. These results suggest that the massive cell death phenomenon called BMN is partially induced by the extrinsic pathway of apoptosis.