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Acute myeloid leukemia (AML) is a heterogeneous blood-related neoplasm that predominantly afflicts older adults with a poor prognosis due to their physical condition and the presence of medical accompanying comorbidities, adverse biological disease features, and suitability for induction intensive chemotherapy and allogenic stem cells transplantation. Recent research into the molecular and biological factors contributing to disease development and progression has led to significant advancements in treatment approaches for older patients with AML. This review article discusses the latest biological and therapeutic developments that are transforming the management of AML in older adults. [ABSTRACT FROM AUTHOR]

This article, published in the British Journal of Haematology, discusses a novel IDH2-R159H mutation found in a patient with acute myeloid leukaemia (AML). The mutation was acquired during disease progression and had a significant impact on cell metabolism and differentiation. The study also explores the sensitivity of the mutation to enasidenib, an oral inhibitor of mutant IDH2. The findings suggest that the presence of the IDH2-R159H mutation, along with another mutation, may be associated with a negative outcome and reduced response to enasidenib. The authors emphasize the importance of retesting for molecular changes during the course of the disease. [Extracted from the article]

Simple Summary: Acute myeloid leukemia (AML) is characterized by the expansion of clonally derived hematopoietic precursors undergoing a partial or complete maturation block. De novo AML is characterized by recurrent cytogenetic alterations such as chromosomal translocations. However, in the recent past, it was shown that several somatic mutations and epigenetic alterations also contribute to AML onset and progression. Epigenetic mechanisms regulate the equilibrium between self-renewal and differentiation of hematopoietic stem cells and precursors. In this context, Polycomb-group (PcG) proteins regulate the expression of genes involved in cell-cycle regulation and differentiation, and aberrant expression and/or mutations of PcG genes have been shown to occur in hematopoietic neoplasms. In this study we analyzed the expression of Yin and Yang 1 protein (YY1), a member of the noncanonical PcG complexes, in AML patient samples and AML cell lines and the effect of YY1 downregulation on the AML differentiation block. Our results show that YY1 is significantly overexpressed in AML patient samples and AML cell lines and that YY1 knockdown relieves the differentiation block. YY1 downregulation in two AML cell lines (HL-60 and OCI-AML3) and one AML patient sample restored the expression of members of the CEBP protein family, increased the expression of extrinsic growth factors/receptors and surface antigenic markers, induced morphological cell characteristics typical of myeloid differentiation, and sensitized cells to retinoic acid treatment and to apoptosis. Overall, our data show that YY1 is not a secondary regulator of myeloid differentiation but that, if overexpressed, it can play a predominant role in myeloid differentiation block. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute Myeloid Leukemias (AMLs) are rapidly progressive clonal neoplastic diseases. The overall 5-year survival rate is very poor: less than 5% in older patients aged over 65 years old. Elderly AML patients are often "unfit" for intensive chemotherapy, further highlighting the need of highly effective, well-tolerated new treatment options for AMLs. Growing evidence indicates that AML blasts feature a highly diverse and flexible metabolism consistent with the aggressiveness of the disease. Based on these evidences, we targeted the metabolic peculiarity and plasticity of AML cells with an association of ascorbate, which causes oxidative stress and interferes with hexokinase activity, and buformin, which completely shuts down mitochondrial contributions in ATP production. The ascorbate–buformin combination could be an innovative therapeutic option for elderly AML patients that are resistant to therapy. In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias' (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options. [ABSTRACT FROM AUTHOR]

Abstract: Background: Elevated levels of glutathione (GSH) have been reported to play an important role in mediating chemoresistance in tumor cells. The regulation of γ-glutamylcysteine synthetase (γ-GCS) is one of the major determinants of GSH homeostasis. The aim of our study was to investigate γ-GCS gene expression in patients affected by acute myeloid leukemia (AML). Methods: A total of 64 AML samples, including 23 acute promyelocytic leukemia (APL or M3) cases, were included in the study. γ-GCS mRNA levels were determined by real-time quantitative RT-PCR. All patients were evaluated at diagnosis, whereas post-treatment γ-GCS mRNA levels were assessed at the end of the consolidation therapy in 16 cases. Results: Our data showed that variable degrees of γ-GCS expression were detectable in AML, likely reflecting disease heterogeneity; in particular, APL cases, compared to the other AML subsets, showed both significantly lower basal levels of γ-GCS mRNA at presentation and significantly increased mRNA levels after treatment. Conclusions: Decreased levels of γ-GCS leading to reduced GSH may at least in part explain the higher sensitivity of APL to chemotherapy. [Copyright &y& Elsevier]