👤 Keisuke Kirito

IgM-related AL amyloidosis is a rare and distinct clinical entity, often associated with underlying lymphoproliferative disorders such as Waldenström's macroglobulinemia (WM) or lymphoplasmacytic lymphoma (LPL). Unlike non-IgM AL amyloidosis, it exhibits unique organ involvement patterns and generally poorer prognosis. We report a 66-year-old woman diagnosed with WM complicated by systemic IgM-κ AL amyloidosis. She received combination chemotherapy with rituximab and bendamustine (BR), resulting in a reduction of serum IgM levels. Despite the hematologic improvement, her liver dysfunction rapidly progressed, and she died of hepatic failure just two months after diagnosis. Pathological autopsy revealed massive IgM-κ amyloid deposition in the liver and multiple organs, with no residual lymphoma in the bone marrow or lymph nodes. These findings suggest that extensive hepatic amyloid infiltration was already present at diagnosis, and that organ response could not be achieved despite hematologic improvement. This case highlights the aggressive nature of IgM-related AL amyloidosis and the critical importance of early detection, especially when liver dysfunction is observed. Current therapies targeting the underlying clone may not be sufficient in cases with advanced organ involvement, emphasizing the urgent need for novel strategies to facilitate amyloid clearance and protect organ function. Show less

Adenosine monophosphate-activated protein kinase (AMPK) is a sensor for cellular energy status. When the cellular energy level is decreased, AMPK is activated and functions to suppress energy-consuming processes, including protein synthesis. Recently, AMPK has received attention as an attractive molecular target for cancer therapy. Several studies have revealed that the activation of AMPK by chemical stimulators, such as metformin, induces apoptosis in a variety of hematologic malignant cells. From another perspective, these results suggest that the function of AMPK is impaired in hematologic tumor cells. However, the precise mechanisms by which this impairment occurs are not well understood. In melanoma cells, oncogenic BRAF constitutively activates the extracellular signal-regulated kinase (ERK) pathway and phosphorylates liver kinase B1, an upstream activator of 5' adenosine monophosphate-activated protein kinase (AMPK), resulting in the inactivation of liver kinase B1 and AMPK. In this study, we analyzed whether ERK is involved in the suppression of AMPK activity using established and primary human leukemia cells. We found an inverse correlation between the intensity of ERK activity and the degree of AMPK activation after stimulation with either glucose deprivation or metformin. We also found that the inhibition of ERK activity by U0126 restored AMPK activation after metformin treatment. Furthermore, a combined treatment with metformin and U0126 enhanced the antileukemic activity of metformin. Importantly, metformin induced ERK activation by suppressing the protein levels of dual specificity phosphatase 6, a negative regulator of ERK. This crosstalk between AMPK and ERK could diminish the antileukemic activity of metformin. Taken together, our present observations suggest a novel therapeutic strategy for improving the efficacy of metformin in treating leukemia. Show less