2. Academic Validation
  3. Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen

Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen

  • Elife. 2020 Oct 1;9:e57858. doi: 10.7554/eLife.57858.
Hao Zhang  # 1 2,  Yang Zhang  # 3 4,  Xinyue Zhou  # 1 2,  Shaela Wright 3 4,  Judith Hyle 3 4,  Lianzhong Zhao 1 2,  Jie An 1 2,  Xujie Zhao 5,  Ying Shao 6,  Beisi Xu 6,  Hyeong-Min Lee 7,  Taosheng Chen 7,  Yang Zhou 8,  Xiang Chen 6,  Rui Lu 1 2,  Chunliang Li 3 4
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, United States.
  • 2 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, United States.
  • 3 Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, United States.
  • 4 Cancer Biology Program/Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, United States.
  • 5 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, United States.
  • 6 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States.
  • 7 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, United States.
  • 8 Department of Biomedical Engineering School of Engineering, University of Alabama at Birmingham, Birmingham, United States.
  • # Contributed equally.
PMID: 33001025 DOI: 10.7554/eLife.57858
Abstract

Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, notably those with KMT2A (MLL) gene rearrangements. 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. Here, we generated the HOXA9-mCherry knock-in reporter cell lines to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2, whose depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of Hoxa9 rescued impaired leukemia cell proliferation upon USF2 loss. Cut and Run analysis revealed the direct occupancy of USF2 at 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.

Keywords

CRISPR screen; HOXA9; cancer biology; human; knock-in; mll-rearranged leukemia; transcriptional regulation.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z