A genome-scale in vivo loss-of-function screen identifies <i>Phf6</i> as a lineage-specific regulator of leukemia cell growth

Meacham, Corbin E.; Lawton, Lee N.; Soto‐Feliciano, Yadira M.; Pritchard, Justin R.; Joughin, Brian A.; Ehrenberger, Tobias; Fenouille, Nina; Zuber, Johannes; Williams, Richard; Young, Richard A.; Hemann, Michael T.

doi:10.1101/gad.254151.114

Cited by 65 publications

(89 citation statements)

References 37 publications

(36 reference statements)

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“…Inactivating mutations in PHF6 were subsequently identified in human leukemia of the T and myeloid lineages, highlighting its role as a tumor suppressor gene in these malignancies (Van Vlierberghe et al 2010, 2011. Our group recently described a tumor-promoting role for Phf6 in a murine model of BCR-ABL1 + B-ALL (Williams et al 2006;Meacham et al 2015). In this study, we found that hairpin-mediated knockdown of Phf6 leads to impaired growth of B-ALL cells in vivo.…”

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confidence: 54%

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

et al. 2017

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Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell-and T-cell-specific factors. Additionally, Phf6KO cells show significant downregulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.

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confidence: 54%

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

et al. 2017

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“…This is signifi cantly different from the currently used model systems, mainly cancer cell lines (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and might provide novel insights into mechanisms of tumor maintenance.…”

Section: Discussionmentioning

confidence: 78%

“…Unfortunately, however, this information is available for only a fraction of the mutated cancer genes. Loss-of-function experiments targeting multiple genes were extensively used to investigate tumor vulnerabilities in vivo , using either cancer cell lines or genetically engineered tumors which, however, do not refl ect the genetic diversity of human malignancies (5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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The identifi cation of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the fi rst in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specifi c shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth ( ∼ 50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identifi ed genes, the Histone-lysine N-methyltransferase KMT2D , and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specifi c, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways. SIGNIFICANCE:Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specifi c signaling pathways are activated in tumors. Cancer Discov;6(6);

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“…This effect is reminiscent of RUNX1 mutations in myelodysplastic syndrome, which reduce rRNA synthesis and ribosomal biogenesis, tune down p53 levels, and render hematopoietic stem cells more resilient to stress-induced apoptosis (56). Interestingly, the PHF6 protein, which, like FGF13, interacts with UBF and represses rRNA synthesis (55), is overexpressed in B-cell lymphoma and has been suggested to play a role in progression of this malignancy (57), often driven by c-Myc hyperactivation.…”

Section: Fgf13 Depletion Augments Nucleolar Size and Increases Rrna Andmentioning

confidence: 99%

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Bublik

Bursać

Sheffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

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A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage-specific regulator of leukemia cell growth

Cited by 65 publications

References 37 publications

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

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