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Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation [scRNA-seq]

ABSTRACT: Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation [scRNA-seq]

PROVIDER: PRJNA843082 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19431985.fastq.gz	Fastqsanger.gz
	SRR19431986.fastq.gz	Fastqsanger.gz
	SRR19431987.fastq.gz	Fastqsanger.gz

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Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation

Project description:Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation

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Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation [CRISPR]

Project description:Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adaptor of a Cullin-3 RING E3 ubiquitin ligase complex responsible for degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations have been identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 which escape degradation, drive hematopoietic stem cell expansion (HSC) and leukemia in vivo. LZTR1 null cells rely on multiple RAS GTPases for transformation. Consequently, RAS targeting bioPROTACs or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data thereby reveal proteolysis of non-canonical RAS proteins as novel regulators of HSC function, define the function and spectrum of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation.

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Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation [scRNA-seq]

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Impaired proteolysis of non-canonical RAS proteins drives clonal hematopoietic transformation

Project description:This SuperSeries is composed of the SubSeries listed below.

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Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation.

Project description:Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation.SignificanceHere we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia. This article is highlighted in the In This Issue feature, p. 2221.

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Project description:Though limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, however the specific genomic sites targeted for H3NT proteolysis and their functional significance of H3NT cleavage remain unknown.We used genome wide Chip-seq (ChIPac-Seq) approaches to an established cell model of osteoclast differentiation. We discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most of these H3NT-cleaved genes are epigenetically regulated during osteoclastogenesis.We also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9).Abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. In summary our results support the necessity of MMP-9-dependent H3NT proteolysis in the epigenetic reprogramming of gene pathways required for proficient osteoclastogenesis.

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Project description:The differential expression of microRNAs in Ras transformed epithelial cells of human and rat origin was investigated. Here we describe the group of miRNAs differentially expressed in two Ras transformed cell lines and defined it as a miRNA Ras signatures. We show that expression of these miRNAs are also affected in different primary tumors with high frequency of Ras mutation. We demonstate that introduction of different miRNAs lost during Ras transformation have big influence on cellular phenotype and mRNA expression. Importance of Ras pathway dependent transcription factors for miRNA regulation was shown as well. The complexity of miRNA – signal transduction pathways interactions and importance of miRNA regulation in Ras dependent malignant tumor formation is discussed.

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