Ik-Chan Song

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Objective The prognostic value of the mutation types and dynamics of FLT3 ‐ITD in acute myeloid leukemia (AML) and other known factors were studied. Methods Initial and follow‐up samples from 45 AML patients with FLT3 ‐ITD mutations were analyzed by fragment length analysis, Sanger sequencing, and next‐generation sequencing. Results Some patients (13%) had multiple FLT3 ‐ITD mutations, and many of them had acute promyelocytic leukemia (APL). FLT3 ‐ITD mutations were classified according to mutation types, including duplication‐only FLT3 ‐ITD (52%) and FLT3 ‐ITD with duplications and insertions (dup + ins) (48%). The dup + ins FLT3 ‐ITD variant was independently associated with poor prognosis among non‐APL patients (odds ratio, 2.92) in addition to FLT3 ‐ITD with ≥50% variant allele frequency (VAF). The VAFs of FLT3 ‐ITD were low (median 2.2%) when detected during morphologic complete remission (CR) after conventional chemotherapy; however, in two patients treated with gilteritinib after relapse, the VAFs of FLT3 ‐ITD were much higher (>95% and 8.1%) in the morphologic CR state. Conclusions The type of FLT3 ‐ITD mutation is important in prognosis, and the dup + ins type of FLT3 ‐ITD can be an indicator of poor prognosis. In addition, the FLT3 ‐ITD mutation status may unexpectedly not match the morphologic examination results after gilteritinib treatment.