Make your cake and eat it: refueling of immune fitness in AML post allo-HCT using baking soda

Although there has been a recent renaissance in the availability of new therapeutic options for patients with acute myeloid leukemia (AML), survival rates remain low coupled with a high incidence of relapse. Enhancing T cell and immune function has become an effective therapeutic approach in hematological malignancies. However, AML cells can modulate the bone marrow microenvironment by changing extracellular nutrient and biochemical availability which can metabolically regulate immune function. Here we review the findings by Uhl et al. showing that T cell metabolism and function can be boosted by treatment with sodium bicarbonate to counteract the metabolic changes induced by lactic acid produced by leukemia cells

Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia

Relapse following a short clinical response to therapy is the major challenge for the management of acute myeloid leukemia (AML) patients. Leukemic stem cells (LSC), as the source of relapse, have been investigated for their metabolic preferences and their alterations at the time of relapse. As LSC rely on oxidative phosphorylation (OXPHOS) for energy requirement, reactive oxygen species (ROS), as by-products of OXPHOS, have been investigated for their role in the effectiveness of the standard AML therapy. Increased levels of non-mitochondrial ROS, generated by nicotinamide adenine dinucleotide phosphate oxidase, in a subgroup of AML patients add to the complexity of studying ROS. Although there are various studies presenting the contribution of ROS to AML pathogenesis, resistance, and its inhibition or activation as a target, a model that can clearly explain its role in AML has not been conceptualized. This is due to the heterogeneity of AML, the dynamics of ROS production, which is influenced by factors such as the type of treatment, cell differentiation state, mitochondrial activity, and also the heterogeneous generation of non-mitochondrial ROS and limited available data on their interaction with the microenvironment. This review summarizes these challenges and the recent progress in this field

Reactive Oxygen Species and Metabolic Re-Wiring in Acute Leukemias

Reactive oxygen species (ROS) is the collective term for several oxygen containing free radicals, such as hydrogen peroxide. ROS is important in innate immunity, protein folding in the endoplasmic reticulum and as a cell signalling molecule involved in cellular proliferation, survival, differentiation, and gene expression. ROS has been implicated in both hematopoietic stem cell quiescence and hematopoietic differentiation. Consequently, ROS is of considerable interest as a therapeutic target, with both pro-oxidant and anti-oxidant cellular modulation being explored. Recently, it has been established that increased ROS production in acute myeloid leukemia (AML) leads to increased glycolysis and metabolic reprogramming. It is often stated as a key tenet of the Warburg effect, that transformed cells, including AML, show increased aerobic glycolysis accompanied by increased cellular glucose uptake and lactate secretion. This review will summarize ROS state of the art in acute leukemia and how these reactive molecules re-wire metabolism in cancer cells. The review will focus on what are ROS? What are the sources of ROS in hematopoietic cells and their function and how this relates to the Warburg effect and regulation of metabolic pathways in acute leukemias

TET-2 up-regulation is associated with the anti-inflammatory action of Vicenin-2

Vicenin-2, a C-glycoside flavone that is present in many plant sources, exerts potent anti-inflammatory effects in a number of cell and animal models of inflammation. Ten-eleven translocation (TET)-2 has recently gained considerable attention due to the role it plays in regulating the inflammasome. We studied the ability of Vicenin-2 (V-2) to regulate a range of lipopolysaccharide (LPS) stimulated inflammatory activities in PMA-differentiated THP-1 cells and human primary mononuclear cells. We also investigated the action of V-2 on the secretion of NLRP3 inflammasome regulated cytokines (IL-1β and IL-18) by ELISA, and determined if V-2 can regulate the expression of NLRP3, IL-10, IL-1Ra and TET-2. The effect of V-2 on NF-κB signalling was investigated by fluorescence microscopy and gene reporter assay. Additionally, the effect of V-2 on LPS-induced phosphorylation of IKB-α was also investigated by Western blot analysis. V-2 down-regulated LPS-induced secretion of proinflammatory cytokines (TNF-α and IL-1β), in both THP-1 and primary mononuclear cells. V-2 also decreased the LPS-stimulated secretion of IL-18 in THP-1 cells. V-2 significantly down-regulated TNF-α induced NF-κB reporter activity in HEK293T transfected cells and attenuated IKB-α phosphorylation in THP-1 cells. V-2 treatment also induced enhanced nuclear staining of the p50 subunit and reduced p65 subunit of NF-κB. V-2 treatment alone increased the expression of anti-inflammatory cytokine, IL-10, and the regulator of the inflammasome; IL-1Ra, in the presence of LPS. V-2 also significantly decreased LPS-induced NLRP3 expression while concomitantly increasing TET-2 expression. This study demonstrates that the anti-inflammatory actions of V-2 are associated not only with increased IL-10 and IL-1Ra expression, but also with TET-2 up-regulation. Further work is required to establish if the effects of V-2 can be definitively linked to TET-2 activity and that these actions are mirrored in a range of relevant cell types

The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts

PDK1 is a master kinase that activates at least six protein kinase groups including AKT, PKC and S6K and is a potential target in the treatment of a range of malignancies. Here we show overexpression of PDK1 in over 40% of myelomonocytic acute leukemia patients. Overexpression of PDK1 occurred uniformly throughout the leukemic population, including putative leukemia-initiating cells. Clinical outcome analysis revealed PDK1 overexpression was associated with poorer treatment outcome. Primary acute myeloid leukemia blasts over-expressing PDK1 showed improved in vitro survival and ectopic expression of PDK1 promoted the survival of myeloid cell lines. Analysis of PDK1 target kinases revealed that PDK1 overexpression was most closely associated with increased phosphorylation of PKC isoenzymes and inhibition of PKC strongly inhibited the survival advantage of PDK1 over-expressing cells. Membrane localization studies implicated PKCα as a major target for PDK1 in this disease. PDK1 over-expressing blasts showed differential sensitivity to PDK1 inhibition (in the low micromolar range) suggesting oncogene addiction, whilst normal bone marrow progenitors were refractory to PDK1 inhibition at effective inhibitor concentrations. PDK1 inhibition also targeted subpopulations of leukemic blasts with a putative leukemia-initiating cell phenotype. Together these data show that overexpression of PDK1 is common in acute myelomonocytic leukemia and is associated with poorer treatment outcome, probably arising from the cytoprotective function of PDK1. We also show that therapeutic targeting of PDK1 has the potential to be both an effective and selective treatment for these patients, and is also compatible with current treatment regimes

Reactive oxygen species rewires metabolic activity in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease with poor clinical outcomes. We have previously shown that constitutive activation of NADPH oxidase 2 (NOX2), resulting in over-production of reactive oxygen species (ROS), occurs in over 60% of AML patients. We have also shown that increased ROS production promotes increased glucose uptake and proliferation in AML cells, mediated by changes in carbohydrate metabolism. Given that carbohydrate, lipid, and protein metabolisms are all intricately interconnected, we aimed to examine the effect of cellular ROS levels on these pathways and establish further evidence that ROS rewires metabolism in AML. We carried out metabolomic profiling of AML cell lines in which NOX2-derived ROS production was inhibited and conversely in cells treated with exogenous H2O2. We report significant ROS-specific metabolic alterations in sphingolipid metabolism, fatty acid oxidation, purine metabolism, amino acid homeostasis and glycolysis. These data provide further evidence of ROS directed metabolic changes in AML and the potential for metabolic targeting as novel therapeutic arm to combat this disease

RUNX1-ETO deregulates the proliferation and growth factor responsiveness of human hematopoietic progenitor cells downstream of the myeloid transcription factor, MYCT1 [Letter]

To elucidate mechanisms by which RUNX1–ETO, the common acute myeloid leukemia t(8;21) fusion protein, primes hematopoietic cells for oncogenic transformation, we previously carried out Affymetrix gene expression profiling of RUNX1–ETO-expressing human CD34+ progenitor cells. We identified the MYC target gene, MYCT1, as a gene significantly upregulated at an early developmental stage that could be integral to RUNX1–ETO-mediated leukemic phenotype. To determine whether increased MYCT1 expression recapitulates the RUNX1–ETO phenotype, we performed retroviral transduction of MYCT1 as a single molecular abnormality into hematopoietic cell lines and normal human cord blood-derived CD34+ progenitor cells. In the absence of commercially available MYCT1 antibody, retroviral expression vectors, containing full-length MYCT1 coding sequence with (MYCT1-HA) or without (MYCT1) the addition of a C-terminal HA antigen tag, were also generated (Supplementary Materials and methods and Supplementary Figure S1), and transgenic MYCT1 over-expression was confirmed at the mRNA and protein levels (Supplementary Figure S2). Functional validation (Supplementary Figure S3) was provided by replication of the reduced viability of MYCT1-expressing murine myeloid 32D cells in the absence of WEHI-3B-conditioned medium reported by Yin et al

I-GUIDE Climbers: A Model for Multidisciplinary Academic Labs for Early Career Development

In this paper, we propose a new form of multidisciplinary academic collaboration that goes beyond the traditional modes of knowledge exchange. We argue that most research collaboration today is based on interactions between closely related disciplines, in which researchers share data, methods, and insights within a common framework or problem. However, such collaboration may not foster the development of the communication and management skills essential to a multi-disciplinary research career. Therefore, we suggest establishing a network of researchers from divergent, yet complementary, disciplines who are interested in improving these skills through regular interactions and feedback. The main goal of this network is not to conduct research or address a specific research question, but to create a learning environment where researchers can enhance their interdisciplinary competencies through the diverse perspectives and experiences of their peers. Moreover, a multidisciplinary group of early-career professionals provides a space for collaborations to flourish. In this paper, we also offer practical advice for researchers who wish to join or create a similar network

A Case report of rare disease Prolidase deficiency in a 15-year-old Pakistan boy

Case presentation Prolidase enzyme plays a crucial role in proline-rich proteins metabolism and physiological processes such as inflammation, cell proliferation, wound healing, angiogenesis, and carcinogenesis. Due to mutations in the peptidase D (PEPD) gene, the catalytic activity of prolidase loss results in prolidase deficiency. Deficiency of prolidase enzyme is an autosomal inborn metabolic rare genetic disorder that has neither any proper treatment nor consensus for treatment. With approximately 100 cases recorded worldwide, the submitted manuscript describes the 2nd recorded case of prolidase deficiency, an extremely uncommon autosomal recessive disorder associated with collagen metabolism, in a 15-year-old Pakistan boy. The disorder typically becomes apparent during infancy. Affected individuals may have enlargement of the spleen (splenomegaly); in some cases, both the spleen and liver are enlarged (hepatosplenomegaly). Diarrhea, vomiting, and dehydration may also occur. People with prolidase deficiency often develop skin lesions, especially on their hands, feet, lower legs, and face. The severity of the skin involvement, which usually begins during childhood, may range from a mild rash to severe skin ulcers. The severity of symptoms in prolidase deficiency varies greatly among affected individuals. Here we present the report of a 15-year-old boy who has all the clinical manifestations of deficiency of prolidase. This is the 2nd case in Pakistan's 229,488,994 million population