The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Matthew Vander G Heiden - One of the best experts on this subject based on the ideXlab platform.
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the role of Pyruvate Kinase m2 in cancer metabolism
Brain Pathology, 2015Co-Authors: Matthew Vander G Heiden, Vivian M LiuAbstract:The M2 isoform of Pyruvate Kinase is expressed preferentially in cancer cells over other Pyruvate Kinase isoforms. PKM2 is unique in its ability to be regulated allosterically by nutrients and growth signaling pathways, allowing cells to adapt their metabolic program to match physiological needs in different environments. Here, we discuss the role of Pyruvate Kinase M2 in glioma and in cancer metabolism.
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Pyruvate Kinase function regulation and role in cancer
Seminars in Cell & Developmental Biology, 2015Co-Authors: William J Israelsen, Matthew Vander G HeidenAbstract:Pyruvate Kinase is an enzyme that catalyzes the conversion of phosphoenolPyruvate and ADP to Pyruvate and ATP in glycolysis and plays a role in regulating cell metabolism. There are four mammalian Pyruvate Kinase isoforms with unique tissue expression patterns and regulatory properties. The M2 isoform of Pyruvate Kinase (PKM2) supports anabolic metabolism and is expressed both in cancer and normal tissue. The enzymatic activity of PKM2 is allosterically regulated by both intracellular signaling pathways and metabolites; PKM2 thus integrates signaling and metabolic inputs to modulate glucose metabolism according to the needs of the cell. Recent advances have increased our understanding of metabolic regulation by Pyruvate Kinase, raised new questions, and suggested the possibility of non-canonical PKM2 functions to regulate gene expression and cell cycle progression via protein-protein interactions and protein Kinase activity. Here we review the structure, function, and regulation of Pyruvate Kinase and discuss how these properties enable regulation of PKM2 for cell proliferation and tumor growth.
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ml285 affects reactive oxygen species inhibition of Pyruvate Kinase m2
2013Co-Authors: Kyle R Brimacombe, Dimitrios Anastasiou, Bum Soo Hong, Wolfram Tempel, Svetoslav Dimov, Matthew Vander G Heiden, Henrike Veith, Douglas S AuldAbstract:The ability of all cells to regulate levels of reactive oxygen species (ROS) is vital for controlling many aspects of proliferation and survival and we have discovered that Pyruvate Kinase M2 (PKM2) is important for cancer cell biology. PKM2 is directly oxidized on Cys358 to inhibit its catalytic activity, which allows for diversion of glucose-6-phosphate into the pentose phosphate pathway. This, in turn, allows the synthesis of NADPH, which is critical for generating reduced glutathione, necessary for ROS detoxification. In a cellular context, our PKM2 activator, ML285 protects the enzyme from oxidation by ROS and results in sensitization to oxidative stress and increased apoptosis.
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identification of small molecule inhibitors of Pyruvate Kinase m2
Biochemical Pharmacology, 2010Co-Authors: Matthew Vander G Heiden, Heather R Christofk, Eli Schuman, Alexander O Subtelny, Hadar Sharfi, Edward E Harlow, Jun Xian, Lewis C. CantleyAbstract:A common feature of tumors arising from diverse tissue types is a reliance on aerobic glycolysis for glucose metabolism. This metabolic difference between cancer cells and normal cells could be exploited for therapeutic benefit in patients. Cancer cells universally express the M2 isoform of the glycolytic enzyme Pyruvate Kinase (PKM2), and previous work has demonstrated that PKM2 expression is necessary for aerobic glycolysis and cell proliferation in vivo. Because most normal tissues express an isoform of Pyruvate Kinase other than PKM2, selective targeting of PKM2 provides an opportunity to target cell metabolism for cancer therapy. PKM2 has an identical catalytic site as the related M1 splice variant (PKM1). However, isoform selective inhibition is possible as PKM2 contains a unique region for allosteric regulation. We have screened a library of greater than 1,00,000 small molecules to identify such inhibitors. The inhibitors identified for PKM2 fell primarily into three distinct structural classes. The most potent PKM2 inhibitor resulted in decreased glycolysis and increased cell death following loss of growth factor signaling. At least part of this effect was due to on-target PKM2 inhibition as less cell death was observed in cells engineered to express PKM1. These data suggest that isoform selective inhibition of PKM2 with small molecules is feasible and support the hypothesis that inhibition of glucose metabolism in cancer cells is a viable strategy to treat human malignancy.
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Pyruvate Kinase m2 is a phosphotyrosine binding protein
Nature, 2008Co-Authors: Heather R Christofk, Matthew Vander G Heiden, John M Asara, Lewis C. CantleyAbstract:Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of Pyruvate Kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of Pyruvate Kinase is critical for rapid growth in cancer cells.
William J Israelsen - One of the best experts on this subject based on the ideXlab platform.
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Pyruvate Kinase m1 suppresses development and progression of prostate adenocarcinoma
bioRxiv, 2021Co-Authors: Shawn M Davidson, William J Israelsen, Julia E Heyman, James P Obrien, A C Liu, D R Schmidt, Talya L Dayton, R SehgalAbstract:Most cancers, including prostate cancers, express the M2 splice isoform of Pyruvate Kinase (Pkm2). This isoform can promote anabolic metabolism to support cell proliferation; however, Pkm2 expression is dispensable for many cancers in vivo. Pyruvate Kinase M1 (Pkm1) isoform expression is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied. Pkm1 is expressed in normal prostate tissue; thus, to test how differential Pyruvate Kinase isoform expression affects cancer initiation and progression we generated mice harboring a conditional allele of Pkm1 and crossed this allele, as well as a Pkm2 conditional allele, to a Pten loss-driven prostate cancer model. We found that Pkm1 loss leads to Pkm2 expression and accelerates prostate cancer, while deletion of Pkm2 leads to increased Pkm1 expression and suppresses cancer. Consistent with these data, a small molecule Pyruvate Kinase activator that mimics a PKM1-like state suppresses progression of established prostate tumors. PKM2 expression is retained in most human prostate cancers, arguing that pharmacological PKM2 activation may be beneficial for some prostate cancer patients.
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Pyruvate Kinase function regulation and role in cancer
Seminars in Cell & Developmental Biology, 2015Co-Authors: William J Israelsen, Matthew Vander G HeidenAbstract:Pyruvate Kinase is an enzyme that catalyzes the conversion of phosphoenolPyruvate and ADP to Pyruvate and ATP in glycolysis and plays a role in regulating cell metabolism. There are four mammalian Pyruvate Kinase isoforms with unique tissue expression patterns and regulatory properties. The M2 isoform of Pyruvate Kinase (PKM2) supports anabolic metabolism and is expressed both in cancer and normal tissue. The enzymatic activity of PKM2 is allosterically regulated by both intracellular signaling pathways and metabolites; PKM2 thus integrates signaling and metabolic inputs to modulate glucose metabolism according to the needs of the cell. Recent advances have increased our understanding of metabolic regulation by Pyruvate Kinase, raised new questions, and suggested the possibility of non-canonical PKM2 functions to regulate gene expression and cell cycle progression via protein-protein interactions and protein Kinase activity. Here we review the structure, function, and regulation of Pyruvate Kinase and discuss how these properties enable regulation of PKM2 for cell proliferation and tumor growth.
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pkm2 isoform specific deletion reveals a differential requirement for Pyruvate Kinase in tumor cells
Cell, 2013Co-Authors: William J Israelsen, Shawn M Davidson, Talya L Dayton, Brian P Fiske, Aaron M Hosios, Gary Bellinger, Jie Li, Yimin Yu, Mika Sasaki, James W HornerAbstract:Summary The Pyruvate Kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1 -loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable Pyruvate Kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active Pyruvate Kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells. PaperClip
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pkm2 isoform specific deletion reveals a differential requirement for Pyruvate Kinase in tumor cells
Cell, 2013Co-Authors: William J Israelsen, Shawn M Davidson, Talya L Dayton, Brian P Fiske, Aaron M Hosios, Gary Bellinger, Mika Sasaki, James W Horner, Laura N Burga, Jianxin XieAbstract:The Pyruvate Kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable Pyruvate Kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active Pyruvate Kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.
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Pyruvate Kinase m2 activators promote tetramer formation and suppress tumorigenesis
Nature Chemical Biology, 2012Co-Authors: Dimitrios Anastasiou, William J Israelsen, Jian Kang Jiang, Matthew B Boxer, Bum Soo Hong, Wolfram Tempel, Svetoslav Dimov, Min Shen, Abhishek K Jha, Hua YangAbstract:Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of Pyruvate Kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high Pyruvate Kinase activity may suppress tumor growth. We show that expression of PKM1, the Pyruvate Kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.
Sybille Mazurek - One of the best experts on this subject based on the ideXlab platform.
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Pyruvate Kinase m2 and cancer an updated assessment
FEBS Letters, 2014Co-Authors: Mohd Askandar Iqbal, Sybille Mazurek, Vibhor Gupta, Prakasam Gopinath, Rameshwar N K BamezaiAbstract:Cancer cells are characterized by high glycolytic rates to support energy regeneration and anabolic metabolism, along with the expression of Pyruvate Kinase isoenzyme M2 (PKM2). The latter catalyzes the last step of glycolysis and reprograms the glycolytic flux to feed the special metabolic demands of proliferating cells. Besides, PKM2 has moonlight functions, such as gene transcription, favoring cancer. Accumulating evidence suggests a critical role played by the low-activity-dimeric PKM2 in tumor progression, supported by the identification of mutations which result in the down-regulation of its activity and tumorigenesis in a nude mouse model. This review discusses PKM2 regulation and the benefits it confers to cancer cells. Further, conflicting views on PKM2’s role in cancer, its therapeutic relevance and future directions in the field are also discussed.
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Pyruvate Kinase type m2 a key regulator of the metabolic budget system in tumor cells
The International Journal of Biochemistry & Cell Biology, 2011Co-Authors: Sybille MazurekAbstract:Cell proliferation only proceeds when metabolism is capable of providing a budget of metabolic intermediates that is adequate to ensure both energy regeneration and the synthesis of cell building blocks in sufficient amounts. In tumor cells, the glycolytic Pyruvate Kinase isoenzyme M2 (PKM2, M2-PK) determines whether glucose is converted to lactate for regeneration of energy (active tetrameric form, Warburg effect) or used for the synthesis of cell building blocks (nearly inactive dimeric form). This review discusses the regulation mechanisms of Pyruvate Kinase M2 expression by different transcription factors as well as the regulation of Pyruvate Kinase M2 activity by direct interaction with certain oncoproteins, tyrosine and serine phosphorylation, binding of phosphotyrosine peptides, association with other glycolytic and non glycolytic enzymes, the promyelocytic leukemia tumor suppressor protein, as well as metabolic intermediates. An intervention in the regulation mechanisms of the expression, activity and tetramer to dimer ratio of Pyruvate Kinase M2 has severe consequences for metabolism as well as proliferation and tumorigenic capacity of the cells which makes this enzyme a promising target for potential therapeutic approaches. The quantification of the dimeric form of Pyruvate Kinase M2 (Tumor M2-PK) in plasma and stool allows early detection of tumors and therapy control. Several different mechanisms may induce a translocation of Pyruvate Kinase M2 into the nucleus. The role of Pyruvate Kinase M2 in the nucleus is complex as witnessed by evidence of its effect both as pro-proliferative as well as pro-apoptotic stimuli.
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faecal tumour m2 Pyruvate Kinase a new sensitive screening tool for colorectal cancer
British Journal of Cancer, 2004Co-Authors: Philip D Hardt, Sybille Mazurek, M Toepler, P Schlierbach, R G Bretzel, Erich Eigenbrodt, H U KloerAbstract:One alteration consistently found during tumour formation, including gastrointestinal tumours, is the upregulation of glycolytic enzymes. This upregulation takes place at the RNA and protein level, as well as at the level of enzymatic activities (Durany et al, 1997; Eigenbrodt et al, 1997; Mazurek et al, 2000; Hegde et al, 2001; Atsumi et al, 2002; Birkenkamp-Demtroder et al, 2002; Williams et al, 2003). In addition, in the case of the glycolytic enzyme Pyruvate Kinase, a loss of the tissue-specific isoenzymes (L-PK in the liver, M1-PK in muscle and brain and R-PK in erythrocytes) and expression of the Pyruvate Kinase isoenzyme type M2 (M2-PK) is described in all tumours investigated thus far (Figure 1A) (Staal and Rijksen, 1991; Mazurek et al, 1997; Steinberg et al, 1999). The increase in M2-PK levels has been recorded by the determination of enzymatic activities, cellulose acetate electrophoresis, Western blotting and immunohistology (Reinacher and Eigenbrodt, 1981; Staal and Rijksen, 1991; Eigenbrodt et al, 1992; Mazurek et al, 2000). In healthy tissues, all isoenzymes of Pyruvate Kinase consist of four subunits whereby hybrids of the different forms can also occur (Saheki et al, 1978, 1979). Whereas in the epithelium of the upper gastrointestinal tract (oesophagus and stomach) hybrids between M1 and M2 have been found, the lower gastrointestinal tract (jejunum, colon and rectum) is characterised by hybrids of L and M2-PK (Saheki et al, 1978, 1979). In gastrointestinal tumours, only subunits of the type M2 are detectable and Pyruvate Kinase is mainly in the dimeric form (Mazurek et al, 2000). Therefore, the dimeric form of M2-PK has been termed Tumour M2-PK. The tetramer : dimer ratio of M2-PK can be quantified by gel permeation, isoelectric focusing or by ELISA (Cerwenka et al, 1999; Schulze, 2000; Mazurek et al, 1997, 2001; Mazurek and Eigenbrodt, 2003). The upregulation of the M2-PK protein is under the control of HIF-1 and ras, which are both consistently altered in gastrointestinal tumours (Kress et al, 1998; Mazurek et al, 2001; Nishikawa et al, 2002; Mazurek and Eigenbrodt, 2003). The tetramer : dimer ratio of M2-PK is under the control of several oncoproteins, such as pp60v−src Kinase, HPV-16 E7 and A-Raf (Figure 1B) (Eigenbrodt et al, 1998b; Zwerschke et al, 1999; Le Mellay et al, 2002). Interestingly, pp60c−src Kinase and A-Raf are consistently altered in gastrointestinal tumours (Bolen et al, 1987; Iravani et al, 1998; Irby et al, 1999; Luckett et al, 2000; Dehm et al, 2001; Dhillon et al, 2003).
James W Horner - One of the best experts on this subject based on the ideXlab platform.
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pkm2 isoform specific deletion reveals a differential requirement for Pyruvate Kinase in tumor cells
Cell, 2013Co-Authors: William J Israelsen, Shawn M Davidson, Talya L Dayton, Brian P Fiske, Aaron M Hosios, Gary Bellinger, Jie Li, Yimin Yu, Mika Sasaki, James W HornerAbstract:Summary The Pyruvate Kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1 -loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable Pyruvate Kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active Pyruvate Kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells. PaperClip
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pkm2 isoform specific deletion reveals a differential requirement for Pyruvate Kinase in tumor cells
Cell, 2013Co-Authors: William J Israelsen, Shawn M Davidson, Talya L Dayton, Brian P Fiske, Aaron M Hosios, Gary Bellinger, Mika Sasaki, James W Horner, Laura N Burga, Jianxin XieAbstract:The Pyruvate Kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable Pyruvate Kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active Pyruvate Kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.
Rachael F Grace - One of the best experts on this subject based on the ideXlab platform.
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the variable manifestations of disease in Pyruvate Kinase deficiency and their management
Haematologica, 2020Co-Authors: Hanny Alsamkari, Paola Bianchi, Wilma Barcellini, Eduard J Van Beers, Kevin H M Kuo, Bertil Glader, Maria Del Mar Mañú-pereira, Richard Van Wijk, Andreas Glenthoj, Rachael F GraceAbstract:Pyruvate Kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including Pyruvate Kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell Pyruvate and ATP deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
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safety and efficacy of mitapivat in Pyruvate Kinase deficiency
The New England Journal of Medicine, 2019Co-Authors: Rachael F Grace, Yaddanapudi Ravindranath, Christian Rose, Mark D Layton, Frederic Galacteros, Wilma Barcellini, Holmes D Morton, Eduard J Van Beers, Hassan M Yaish, Kevin H M KuoAbstract:Abstract Background Pyruvate Kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of Pyruvate Kinase ...
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How we manage patients with Pyruvate Kinase deficiency.
British journal of haematology, 2019Co-Authors: Rachael F Grace, D. Mark Layton, Wilma BarcelliniAbstract:Novel therapies in development have brought a new focus on Pyruvate Kinase deficiency (PKD), the most common congenital haemolytic anaemia due to a glycolytic enzyme deficiency. With an improved recognition of its clinical presentation and understanding of the diagnostic pathway, more patients are likely to be identified with this anaemia. Complications, including gallstones and non-transfusion-related iron overload, require monitoring for early diagnosis and management. Current management remains supportive with red cell transfusions, chelation and splenectomy. Decisions to transfuse and/or splenectomise must be individualised. Haematopoietic stem cell transplant has been pursued in a small number of patients with mixed outcomes. Novel treatment approaches, which range from a small molecule Pyruvate Kinase activator to gene therapy, may transform the way in which PKD is managed in the future. In this review, we discuss the pathophysiology of PKD and present our approaches to diagnosis, monitoring and management of patients with this anaemia.
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erythrocyte Pyruvate Kinase deficiency 2015 status report
American Journal of Hematology, 2015Co-Authors: Rachael F Grace, Alberto Zanella, Hassan M Yaish, Ellis J Neufeld, Holmes D Morto, Stefa Ebe, Ertil GladeAbstract:Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell Pyruvate Kinase deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.Am. J. Hematol. 90:825–830, 2015. © 2015 Wiley Periodicals, Inc.
