Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The organization of the hematopoietic system is dependent on hematopoietic stem cells (HSCs) that are capable of self-renewal and multilineage differentiation to produce different blood cell lines. Autophagy has a central role in energy production and metabolism of the cells during starvation, cellular stress adaption, and removing mechanisms for aged or damaged organelles. The role and importance of autophagy pathways are becoming increasingly recognized in the literature because these pathways can be useful in organizing intracellular circulation, molecular complexes, and organelles to meet the needs of various hematopoietic cells. There is supporting evidence in the literature that autophagy plays an emerging role in the regulation of normal cells and that it also has important features in malignant hematopoiesis. Understanding the molecular details of the autophagy pathway can provide novel methods for more effective treatment of patients with leukemia. Overall, our review will emphasize the role of autophagy and its different aspects in hematological malignant neoplasms.
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PMID:Autophagy in Hematological Malignancies: Molecular Aspects in Leukemia and Lymphoma. 3263 8

Mixed-lineage leukemia (MLL) fusions are transcriptional activators that induce leukemia, with a dismal prognosis that mandates further elucidation of their transformation mechanism. In this study, knockdown of the direct MLL-ENL target gene polypyrimidine tract binding protein-1 (PTBP1) was rate limiting for cell proliferation and caused a metabolic phenotype associated with reduced glucose consumption and lactate production. This effect was accompanied by a reduction of splice isoform-2 of pyruvate kinase M (PKM2). Because PKM2 restricts glycolytic outflow to provide anabolic intermediates, we tested the consequences of glucose, energy, and Ser/Gly starvation for cell physiology. Administration of deoxyglucose, energetic decoupling with rotenone, and inhibition of Ser biosynthesis by CBR5884 had a significantly stronger influence on self-renewal and survival of transformed cells than on normal controls. In particular, inhibition of Ser synthesis, which branches off glycolysis caused accumulation of reactive oxygen species, DNA damage, and apoptosis, predominantly in leukemic cells. Depletion of exogenous Ser/Gly affected proliferation and self-renewal of murine and human leukemia samples, even though they are classified as nonessential amino acids. Response to Ser/Gly starvation correlated with glucose transport, but did not involve activation of the AMPK energy homeostasis system. Finally, survival times in transplantation experiments were significantly extended by feeding recipients a Ser/Gly-free diet. These results suggest selective starvation as an option for supportive leukemia treatment.
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PMID:Exploitable metabolic dependencies in MLL-ENL-induced leukemia. 3276 58


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