Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

Vukovic, Milica; Guitart, Amélie V.; Sepúlveda, Catarina; Villacreces, Arnaud; O’Duibhir, Eoghan; Panagopoulou, Theano I.; Ivens, Alasdair; Menendez-Gonzalez, Juan Bautista; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E.M.; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L.; Wood, Andrew J.; O’Carroll, Dónal; Ratcliffe, Peter J.; Kranc, Kamil R.

doi:10.1084/jem.20150452

Cited by 70 publications

(62 citation statements)

References 39 publications

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“…These conclusions were reinforced by the analysis of the murine FLT3 ITD -induced myeloproliferative neoplasia, in which HIF-1a loss accelerates and aggravates disease development [62]. Finally, Vukovic et al explored the impact of conditional genetic deletion of HIF-2a or both HIF-1a and HIF-2a at different stages of leukemogenesis, showing that deletion of HIF-2a accelerates development of LSCs and shortens leukemia latency initiated by MLL-AF9 [63]. Furthermore, the accelerated initiation of leukemia caused by HIF-2a deletion was shown in that study to be further potentiated by HIF-1a co-deletion [63].…”

Section: Hypoxia and Hifs In Normal And Lscsmentioning

confidence: 99%

Oxidative stress and hypoxia in normal and leukemic stem cells

Testa

Labbaye

Castelli

et al. 2016

Experimental Hematology

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The main hematopoietic stem cell (HSC) functions, self-renewal and differentiation, are finely regulated by both intrinsic mechanisms such as transcriptional and epigenetic regulators and extrinsic signals originating in the bone marrow microenvironment (HSC niche) or in the body (humoral mediators). The interaction between regulatory signals and cellular metabolism is an emerging area. Several metabolic pathways function differently in HSCs compared with progenitors and differentiated cells. Hypoxia, acting through hypoxia-inducing factors, has emerged as a key regulator of stem cell biology and acts by maintaining HSC quiescence and a condition of metabolic dormancy based on anaerobic glycolytic energetic metabolism, with consequent low production reactive oxygen species (ROS) and high antioxidant defense. Hematopoietic cell differentiation is accompanied by changes in oxidative metabolism (decrease of anaerobic glycolysis and increase of oxidative phosphorylation) and increased levels of ROS. Leukemic stem cells, defined as the cells that initiate and maintain the leukemic process, show peculiar metabolic properties in that they are more dependent on oxidative respiration than on glycolysis and are more sensitive to oxidative stress than normal HSCs. Several mitochondrial abnormalities have been described in acute myeloid leukemia (AML) cells, explaining the shift to aerobic glycolysis observed in these cells and offering the unique opportunity for therapeutic metabolic targeting. Finally, frequent mutations of the mitochondrial isocitrate dehydrogenase-2 (IDH2) enzyme are observed in AML cells, in which the mutated enzyme acts as an oncogenic driver and can be targeted using specific inhibitors under clinical evaluation with promising results.

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Section: Hypoxia and Hifs In Normal And Lscsmentioning

confidence: 99%

Oxidative stress and hypoxia in normal and leukemic stem cells

Testa

Labbaye

Castelli

et al. 2016

Experimental Hematology

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“…However, others have shown that deleting HIF1α in a subset of primary AML leukemic stem cells (LSCs) leads to a decrease in sensitivity of these cells to HIF1α inhibition (7). under hypoxic conditions (35). In our studies, we show that HIF2α was detected in the majority of AML samples and cell lines under normoxic conditions.…”

Section: Discussionmentioning

confidence: 44%

HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia

et al. 2018

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Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia-driven and, through knockdown of MIF, HIF1α and HIF2α, establish that hypoxia supports AML tumor proliferation through HIF1α signaling. In vivo targeting of leukemic cell HIF1α inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2α had no measurable effect on AML blast survival. Functionally, targeted inhibition of MIF in vivo improves survival in models of AML. Here we present a mechanism linking HIF1α to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML.

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“…This may explain the mixed results regarding the role of HIF in leukemia. Deletion of Hif-1α, Hif-2α, or both accelerates the development of AML, but are dispensable for the maintenance of established AML [115]. Consistently, deletion of Hif-1α accelerated AML in three different models [116].…”

Section: Glutamine Metabolism: Leukemia’s Umami Taste Budmentioning

confidence: 95%

Cell intrinsic and extrinsic regulation of leukemia cell metabolism

Jiang

Nakada

2016

Int J Hematol

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consumption through glycolysis even in the presence of oxygen (aerobic glycolysis) was initially hypothesized to be due to defective mitochondria [2]. However, more recent studies have established that many cancer cells harbor and are dependent upon functional mitochondria [3][4][5][6]. The question why cancer cells preferentially use glycolysis, an uneconomical route to produce ATP compared to mitochondrial oxidative phosphorylation, is beginning to be addressed in cancer cells. Glycolysis is not the dominant mechanism for many cancer cells to produce ATP, and ATP production is not the limiting factor for proliferation [7]. Rather, glycolysis offers cancer cells with metabolites essential for rapid division through metabolic pathways that branch away from glycolysis. For example, glucose-6-phosphate can be diverted to the pentose phosphate pathway (PPP) to produce reducing agents NADPH and ribonucleotides [8]. Additionally, 3-phospho-glycerate can enter the one-carbon cycle to generate amino acids, lipids, and reducing agents [9]. Thus, increased glycolysis meets the demand of proliferative cancer cells for anabolism, producing metabolic intermediates through multiple branching pathways. The decision of how cancer cells divert glycolysis intermediates remains elusive, but it is likely to be affected by cellular metabolic state and the environment in which the cancer cells are exposed.The metabolic milieu of the tumor microenvironment dictates the behavior of tumors. Tumors are exposed to nutrient-and oxygen-poor conditions as they grow exponentially due to insufficient vascularization [10]. Metabolic adaptation to these stress conditions is vital for tumor survival and expansion, and as such multiple metabolic regulators that enable metabolic adaptation are dysregulated in cancer. These include the components of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling that feeds into the mechanistic target of rapamycin (mTOR) pathway, Abstract Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change cellular metabolism in a cell-intrinsic manner, priming cells for malignancy. Additionally, cellextrinsic cues from the microenvironment, such as hypoxia, nutrient availability, oxidative stress, and crosstalk from surrounding cells can also affect cancer cell metabolism, and produce metabolic heterogeneity within the tumor. Here, we highlight recent findings revealing the complexity and adaptability of leukemia cells to coordinate metabolism.

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Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

Cited by 70 publications

References 39 publications

Oxidative stress and hypoxia in normal and leukemic stem cells

Oxidative stress and hypoxia in normal and leukemic stem cells

HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia

Cell intrinsic and extrinsic regulation of leukemia cell metabolism

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