FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2407870139> ?p ?o ?g. }

• W2407870139 abstract "Interactions of leukemia cells and their bone marrow (BM) microenvironment are known to play a key role in the survival and growth of leukemic cells. It has been postulated that specific niches provide a sanctuary where subpopulations of leukemic cells evade chemotherapy-induced death and acquire a drug-resistant phenotype. Understanding the cellular and molecular biology of the leukemia stem cell (LSC) niche and of microenvironment/leukemia interactions may provide new targets that allow destruction of LSCs without adversely affecting normal stem cell self-renewal. Key emerging therapeutic targets include chemokine receptors such as CXCR4 and hypoxia-related proteins, as well as the metabolic abnormalities of the leukemia-associated stroma. We have recently reported that CXCR4 inhibition causes leukemia cell dislodgement from CXCL12-producing marrow niches, reduced proliferation and induction of differentiation of AML cells in an in vivo model of AML, translating into pronounced anti-leukemia effects. Studies in murine leukemia models using the hypoxia probe pimonidazole demonstrated extensive areas of hypoxia within leukemic, but not healthy normal, bone marrow. Time-course analysis of bone marrow spaces within calvaria and femurs by multiphoton intravital microscopy (MP-IVM) demonstrated lodging of p190-Bcr/Abl tdTomato cells in close proximity to blood vessels, followed by accumulation of leukemia cells localized within the sinusoidal and marrow spaces resulting in the demise of the animals within 3 weeks. In this model, pimonidazole detected hypoxic areas despite abundant vascular supply in the marrow cavities. In vivo magnetic resonance imaging with hyperpolarized pyruvate showed higher pyruvate-lactate conversion (high glycolytic flux) in leukemic marrows. These findings were supported by significant pimonidazole uptake by the diseased bone marrow in patients with acute leukemia, causing stabilization of HIF-1α in 55% (76/138) of primary AML patients and of its target CA9. Paradoxically, AML cells become highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for their survival, and inhibition of OXPHOS with the novel small molecule complex I inhibitor IACS-10759 inhibits oxygen consumption, eliminates hypoxia in vivo and inhibits AML growth. These findings suggest that altered tumor metabolism underlies the hypoxia observed in leukemias. We postulate that the altered tumor microenvironment within the hypoxic niche cells will influence leukemia development and response to therapy. Hence, targeting key metabolic alterations should be considered in the armamentarium of anti-AML therapies. IACS-10759 is presently completing IND enabling safety/toxicity studies with first in human studies targeting relapsed/refractory AML planned for 2016. Citation Format: Marina Y. Konopleva, Tomasz Zal, Niki M. Zacharias Millward, Byoung-Sik Cho, Karine Harutyunyan, Anna Zal, Hong Mu, Sergej Konoplev, Juliana Benito, Juliana Velez, Carlos Bueso-Ramso, Jennifer Molina, Pratip K. Bhattacharya, Maria Emilia Di Francesco, Joseph Marszalek, Michael Andreeff. Altered metabolism in leukemic microenvironment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL07-01." @default.
• W2407870139 created "2016-06-24" @default.
• W2407870139 creator A5000082629 @default.
• W2407870139 creator A5005332599 @default.
• W2407870139 creator A5010034822 @default.
• W2407870139 creator A5022647201 @default.
• W2407870139 creator A5025568616 @default.
• W2407870139 creator A5034240658 @default.
• W2407870139 creator A5036067544 @default.
• W2407870139 creator A5043947276 @default.
• W2407870139 creator A5047146278 @default.
• W2407870139 creator A5048521277 @default.
• W2407870139 creator A5060688708 @default.
• W2407870139 creator A5066687791 @default.
• W2407870139 creator A5070144169 @default.
• W2407870139 creator A5079262854 @default.
• W2407870139 creator A5083451488 @default.
• W2407870139 creator A5087385646 @default.
• W2407870139 date "2015-12-01" @default.
• W2407870139 modified "2023-09-30" @default.
• W2407870139 title "Abstract PL07-01: Altered metabolism in leukemic microenvironment" @default.
• W2407870139 doi "https://doi.org/10.1158/1535-7163.targ-15-pl07-01" @default.
• W2407870139 hasPublicationYear "2015" @default.
• W2407870139 type Work @default.
• W2407870139 sameAs 2407870139 @default.
• W2407870139 citedByCount "0" @default.
• W2407870139 crossrefType "proceedings-article" @default.
• W2407870139 hasAuthorship W2407870139A5000082629 @default.
• W2407870139 hasAuthorship W2407870139A5005332599 @default.
• W2407870139 hasAuthorship W2407870139A5010034822 @default.
• W2407870139 hasAuthorship W2407870139A5022647201 @default.
• W2407870139 hasAuthorship W2407870139A5025568616 @default.
• W2407870139 hasAuthorship W2407870139A5034240658 @default.
• W2407870139 hasAuthorship W2407870139A5036067544 @default.
• W2407870139 hasAuthorship W2407870139A5043947276 @default.
• W2407870139 hasAuthorship W2407870139A5047146278 @default.
• W2407870139 hasAuthorship W2407870139A5048521277 @default.
• W2407870139 hasAuthorship W2407870139A5060688708 @default.
• W2407870139 hasAuthorship W2407870139A5066687791 @default.
• W2407870139 hasAuthorship W2407870139A5070144169 @default.
• W2407870139 hasAuthorship W2407870139A5079262854 @default.
• W2407870139 hasAuthorship W2407870139A5083451488 @default.
• W2407870139 hasAuthorship W2407870139A5087385646 @default.
• W2407870139 hasConcept C109159458 @default.
• W2407870139 hasConcept C203014093 @default.
• W2407870139 hasConcept C2776107976 @default.
• W2407870139 hasConcept C2778461978 @default.
• W2407870139 hasConcept C2780007613 @default.
• W2407870139 hasConcept C28328180 @default.
• W2407870139 hasConcept C3020616263 @default.
• W2407870139 hasConcept C502942594 @default.
• W2407870139 hasConcept C86803240 @default.
• W2407870139 hasConcept C95444343 @default.
• W2407870139 hasConceptScore W2407870139C109159458 @default.
• W2407870139 hasConceptScore W2407870139C203014093 @default.
• W2407870139 hasConceptScore W2407870139C2776107976 @default.
• W2407870139 hasConceptScore W2407870139C2778461978 @default.
• W2407870139 hasConceptScore W2407870139C2780007613 @default.
• W2407870139 hasConceptScore W2407870139C28328180 @default.
• W2407870139 hasConceptScore W2407870139C3020616263 @default.
• W2407870139 hasConceptScore W2407870139C502942594 @default.
• W2407870139 hasConceptScore W2407870139C86803240 @default.
• W2407870139 hasConceptScore W2407870139C95444343 @default.
• W2407870139 hasLocation W24078701391 @default.
• W2407870139 hasOpenAccess W2407870139 @default.
• W2407870139 hasPrimaryLocation W24078701391 @default.
• W2407870139 hasRelatedWork W1547256385 @default.
• W2407870139 hasRelatedWork W1932804803 @default.
• W2407870139 hasRelatedWork W1933061345 @default.
• W2407870139 hasRelatedWork W2022894865 @default.
• W2407870139 hasRelatedWork W2035535969 @default.
• W2407870139 hasRelatedWork W2081148852 @default.
• W2407870139 hasRelatedWork W2119281301 @default.
• W2407870139 hasRelatedWork W2137210843 @default.
• W2407870139 hasRelatedWork W2140382736 @default.
• W2407870139 hasRelatedWork W2178039206 @default.
• W2407870139 hasRelatedWork W2310887710 @default.
• W2407870139 hasRelatedWork W2518376518 @default.
• W2407870139 hasRelatedWork W2550283491 @default.
• W2407870139 hasRelatedWork W2557819679 @default.
• W2407870139 hasRelatedWork W2577425696 @default.
• W2407870139 hasRelatedWork W2893003059 @default.
• W2407870139 hasRelatedWork W2895922378 @default.
• W2407870139 hasRelatedWork W2899718571 @default.
• W2407870139 hasRelatedWork W2905168591 @default.
• W2407870139 hasRelatedWork W3149794308 @default.
• W2407870139 isParatext "false" @default.
• W2407870139 isRetracted "false" @default.
• W2407870139 magId "2407870139" @default.
• W2407870139 workType "article" @default.