A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence

Lü, Bin; Klingbeil, Olaf; Tarumoto, Yusuke; Somerville, Tim D.D.; Huang, Yuhan; Wei, Yiliang; Wai, Dorothy C.C.; Low, Jason K. K.; Milazzo, Joseph P.; Wu, Xiaoli; Cao, Zhendong; Yan, Xiaomei; Demerdash, Osama E.; Huang, Gang; Mackay, Joel P.; Kinney, Justin B.; Shi, Junwei; Vakoc, Christopher R.

doi:10.1016/j.ccell.2018.10.015

Cited by 61 publications

(63 citation statements)

References 61 publications

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“…SEM cells infected with the pooled library of sgRNAs were collected at day 0 and day 12 to sequence for sgRNA distribution (Figure 6C). In accordance with prior genome-wide CRISPR screens and functional studies in B-ALL, many survival dependent genes were identified in the top 50 genes in our screen including PAX5 , DOT1L , ZFP64 , YY1 , MEF2C , MYC and KMT2A (26, 29, 50, 51). USF2 was ranked as the top 24 th essential gene in MLLr SEM cells (Figure 6D).…”

Section: Resultssupporting

confidence: 83%

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Zhang

Wright

et al. 2020

Preprint

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Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, including human acute myeloid leukemia (AML) and subtypes of acute lymphoblastic leukemia (ALL). HOXA9 overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of HOXA9 regulation in leukemia is limited, hindering development of therapeutic strategies to treat HOXA9-driven leukemia. To mitigate these challenges, we generated the first HOXA9-mCherry knock-in reporter in an MLL-rearranged (MLLr) B-ALL cell line to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 mediated screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2 and its homolog USF1. USF1/USF2 depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of HOXA9-MEIS1 fusion protein rescued the impaired leukemia cell proliferation upon USF2 loss. Cut&Run analysis revealed the direct occupancy of USF2 onto HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

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Section: Resultssupporting

confidence: 83%

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Zhang

Wright

et al. 2020

Preprint

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“…The first identified cancer‐associated TFs were fusion proteins in leukemia cells (Table 1). Accumulating lines of evidence have revealed that these fusion proteins function as drivers of disease onset and progression by inhibiting cell differentiation and maintaining a more stem cell‐like state 4,5 . Recently, cancer‐associated TFs that promote invasiveness and metastasis of solid tumors have also been identified (Table 1).…”

Section: Cancer‐associated Tfs Are a Promising Target For Cancer Therapymentioning

confidence: 99%

Targeting DNA binding proteins for cancer therapy

et al. 2020

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Yoshitomo Shiroma and Ryou-u Takahashi contributed equally to this work.Abbreviations: AEP, AF4 family/ENL family/P-TEFb; ARNT, aryl hydrocarbon receptor nuclear translocator; BRD4, bromodomain-containing protein 4; CBP, CREB-binding protein; DUX4, double homeobox protein 4; ETO, eight-twenty one; EWS, Ewing's sarcoma; FLI1, friend leukemia virus integration 1; HIF, hypoxia-inducible factor; MLL, mixed-lineage leukemia; SOX2, Sry-related high-mobility box 2; STAT3, signal transducer and activator of transcription 3; TF, transcription factor; TRF, telomere-repeat binding factor. AbstractDysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs. K E Y W O R D SDNA binding protein, drug discovery, high-throughput screening, telomere, transcription factor | 1059 SHIROMA et Al.

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“…Another example of clustered homotypic TF binding sites associated with gene control is the binding of ZFP64 to the MLL gene promoter, activating the expression of the chromatin regulator MLL, although in this case ZFP64 shows a limited set of additional direct target genes 32 . CHD4 is an especially abundant nuclear protein in erythroid precursors 33 .…”

Section: Discussionmentioning

confidence: 99%

ZNF410 represses fetal globin by devoted control of CHD4/NuRD

Vinjamur¹,

Yao²,

Cole³

et al. 2020

Preprint

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Major effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects on γ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for the β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex.

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A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence

Cited by 61 publications

References 61 publications

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Functional Interrogation ofHOXA9Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Targeting DNA binding proteins for cancer therapy

ZNF410 represses fetal globin by devoted control of CHD4/NuRD

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