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

Abstract

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.

Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis

“…One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al showed that leukemic cell-eliciting Fasligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al, could be effective for relieving BMN and may be useful for making a reliable disease assessment.…”

Complete Bone Marrow Necrosis with Charcot-Leyden Crystals Caused by Myeloid Neoplasm with Mutated <i>NPM1</i> and <i>TET2</i>

“…The main clinical features of BMN are as follows: bone pain, a fever, cytopenia, elevated LDH, ALP and ferritin, and leukoerythroblastosis (1). Although BMN in hematologic malignancies seems to be associated with microvascular failure due to hypercellular bone marrow and the extrinsic pathway of apoptosis, its pathophysiology has not been fully elucidated (1,8). In patients with hematologic malignancies with BMN, lymphoid malignancy is dominant over myeloid ma-lignancy.…”

Bone Marrow Necrosis and Elevated Plasma Levels of Fas Ligand in a Patient with Aggressive Natural Killer Cell Leukemia

“…Pglycoprotein expressed by NK cells is reported to be responsible for its refractoriness to chemotherapy [8]. On the other hand, Kawa et al [9] introduced immunosuppressive and cytoreductive therapy with prednisolone, cyclosporine A and etoposide to a case of systemic active EBV infection. However, it did not benefit our case and pancytopenia was progressive even though symptoms fell down.…”

“…Although membrane-bound FasL can be converted to a soluble form (sFasL) [1], sFasL is undetectable in the serum of healthy person and that of patients with most subtypes of lymphoma or leukemia. It is contrarily elevated in patients with T-large granular lymphocytic (LGL) leukemia and natural killer (NK) cell lymphoma [2][3][4][5][6], suggesting that Fas-FasL system plays a crucial role in characteristic systemic tissue damage observed in these types of hematological tumor [7][8][9]. We report a case of ANKL accompanied by bone marrow necrosis (BMN) with severe bone pain after granulocyte colony-stimulating factor (G-CSF) administration.…”