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LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)

ABSTRACT: LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)

PROVIDER: PRJNA431217 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6503180.fastq.gz	Fastqsanger.gz
	SRR6503190.fastq.gz	Fastqsanger.gz
	SRR6503181.fastq.gz	Fastqsanger.gz
	SRR6503191.fastq.gz	Fastqsanger.gz
	SRR6503182.fastq.gz	Fastqsanger.gz

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LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia

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LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (RNA-Seq)

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LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia.

Project description:The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. We also found that MEF2C-dependent leukemias are sensitive to on-target chemical inhibition of SIK activity. This study reveals a chemical strategy to block MEF2C function in AML, highlighting how an oncogenic TF can be disabled by targeting of upstream kinases.

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LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia

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2018-03-12 | GSE109493 | GEO

LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)

Project description:Genome-wide binding/occupancy profiling by high throughput sequencing

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LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (RNA-Seq)

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Gene expression profiles of Lkb1 WT and KO hematopoietic stem cells (HSCs)

Project description:LKB1 encodes a Ser/Thr kinase and acts as an evolutionarily conserved sensor of cellular energy status in eukaryotic cells. LKB1 functions as the major upstream kinase to phosphorylate AMPK and 12 other AMPK-related kinases, which is required for their activation in many cellular contexts. Once activated, AMPK and AMPK-related kinases phosphorylate a diverse array of downstream effectors to switch on ATP-generating catabolic processes and switch off ATP-consuming anabolic processes, thus restoring energy balance during periods of energetic stress. To study the role and mechanisms of Lkb1 in the regulation of hematopoietic stem cell (HSC) biology, we performed transcriptome analysis of sorted LSK (Lin-, Sca-1+, c-Kit+) cells from Lkb1 WT and KO bone marrows at 1 day post-completing tamoxifen injection (DPI). To identify more proximal molecular effects, we chose 1 DPI due to the modest phenotypes in Lkb1 KO mice, yet documentation of efficient Lkb1 deletion in LSK cells at this very early time point. We treated Lkb1 L/L rosa26CreERT2 and Lkb1 L/L mice (C57BL/Ka-CD45.2:Thy-1.1 background) with Tamoxifen for 5 days to somatically delete Lkb1 in adult mice, and generated Lkb1 WT and KO mice. At 1 DPI, we prepared single-cell suspensions from bone marrow (from femoral and tibial bones), and stained and sorted LSK populations using FACSAria (Becton Dickinson, Mountain View, CA). The RNA was extracted from sorted LSK cells, amplified and subjected to gene profiling. The samples include 3 Lkb1 WT (Lkb1 WT 5-7) and 4 Lkb1 KO (Lkb1 KO 4-7) replicates.

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