CRISPR/Cas9 screens reveal that hexokinase 2 enhances cancer stemness and tumorigenicity
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ABSTRACT:
PROVIDER: PRJNA766529 | ENA |
REPOSITORIES: ENA
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Project description:Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or MLL gene rearrangement (MLL-r) share transcriptomic profiles featured with stemness-related gene signatures and display poor prognosis in the clinic. However, the molecular underpinnings of AML aggressiveness and stemness remain far from clear. Here, we report that the enzymatic activity of Polycomb Repressive Complex 2 (PRC2) is crucial for maintenance of tumorigenicity in NUP98-NSD1+ AML, consistent to its role in MLL-r AML. Transcriptomic analysis revealed Kdm5b, a lysine demethylase gene carrying the “bivalent domain” chromatin feature in AML, to be directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion in AML not only promoted tumorigenicity but also significantly attenuated anti-AML effects by PRC2 inhibitors, thus demonstrating an involvement of the PRC2-|Kdm5b axis for AML oncogenesis. Lower KDM5B expression is positively correlated with poorer prognosis of human AML patients. RNA-seq, ChIP-seq and CUT&RUN based genomic profilings also showed that Kdm5b directly binds to and represses AML stemness genes. In contrast to an essential involvement for its various chromatin-associating domains, Kdm5b’s demethylase function was found to be dispensable for AML suppression, indicating a scaffold role in assembling gene-repressive complexes. Collectively, this study describes a molecular axis involving histone modifiers (PRC2 and Kdm5b) for sustaining the malignant features of AML, implicative of potential therapeutics.
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Project description:Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or MLL gene rearrangement (MLL-r) share transcriptomic profiles featured with stemness-related gene signatures and display poor prognosis in the clinic. However, the molecular underpinnings of AML aggressiveness and stemness remain far from clear. Here, we report that the enzymatic activity of Polycomb Repressive Complex 2 (PRC2) is crucial for maintenance of tumorigenicity in NUP98-NSD1+ AML, consistent to its role in MLL-r AML. Transcriptomic analysis revealed Kdm5b, a lysine demethylase gene carrying the “bivalent domain” chromatin feature in AML, to be directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion in AML not only promoted tumorigenicity but also significantly attenuated anti-AML effects by PRC2 inhibitors, thus demonstrating an involvement of the PRC2-|Kdm5b axis for AML oncogenesis. Lower KDM5B expression is positively correlated with poorer prognosis of human AML patients. RNA-seq, ChIP-seq and CUT&RUN based genomic profilings also showed that Kdm5b directly binds to and represses AML stemness genes. In contrast to an essential involvement for its various chromatin-associating domains, Kdm5b’s demethylase function was found to be dispensable for AML suppression, indicating a scaffold role in assembling gene-repressive complexes. Collectively, this study describes a molecular axis involving histone modifiers (PRC2 and Kdm5b) for sustaining the malignant features of AML, implicative of potential therapeutics.
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Project description:Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or MLL gene rearrangement (MLL-r) share transcriptomic profiles featured with stemness-related gene signatures and display poor prognosis in the clinic. However, the molecular underpinnings of AML aggressiveness and stemness remain far from clear. Here, we report that the enzymatic activity of Polycomb Repressive Complex 2 (PRC2) is crucial for maintenance of tumorigenicity in NUP98-NSD1+ AML, consistent to its role in MLL-r AML. Transcriptomic analysis revealed Kdm5b, a lysine demethylase gene carrying the “bivalent domain” chromatin feature in AML, to be directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion in AML not only promoted tumorigenicity but also significantly attenuated anti-AML effects by PRC2 inhibitors, thus demonstrating an involvement of the PRC2-|Kdm5b axis for AML oncogenesis. Lower KDM5B expression is positively correlated with poorer prognosis of human AML patients. RNA-seq, ChIP-seq and CUT&RUN based genomic profilings also showed that Kdm5b directly binds to and represses AML stemness genes. In contrast to an essential involvement for its various chromatin-associating domains, Kdm5b’s demethylase function was found to be dispensable for AML suppression, indicating a scaffold role in assembling gene-repressive complexes. Collectively, this study describes a molecular axis involving histone modifiers (PRC2 and Kdm5b) for sustaining the malignant features of AML, implicative of potential therapeutics.
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Project description:Acute myeloid leukaemia (AML) continues to have a very high mortality and its treatment hasnot changed for more than 20 years.Here, we propose to apply genomic-wide screens to directly identify therapeutic vulnerabilitiesof AML using AML cells lines with pre-defined somatic mutations. Our studies will be basedon genome-wide CRISPR/CAs9 gRNA screens and will be used to identify drivers of drugresistance to standard chemotherapies.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
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Project description:Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells (ISCs) of the mammalian intestine. Like HFD, ex vivo treatment of intestinal organoid cultures with palmitic acid (PA), a constituent of the HFD, enhances the self-renewal potential of these organoid bodies. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta signature in intestinal stem and progenitor cells and pharmacologic activation of PPAR-delta recapitulates the effects that HFD has on these cells. Interestingly, HFD- and agonist-activated PPAR-delta signaling endows organoid-initiating capacity to non-stem cells and enforced PPAR-delta signaling permits these non-stem cells to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells but also their capacity to initiate tumors. mRNA profiles of intestinal stem cells (GFP-Hi) and progenitors (GFP-Low) from WT or HFD fed mice were generated by deep sequencing using HiSeq 2000.
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