CaMK2D is a critical regulator of coactivation of leukemia stem cell factors in acute myeloid leukemia.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA675223 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13003976_1.fastq.gz | Fastqsanger.gz | |||
| SRR13003976_2.fastq.gz | Fastqsanger.gz | |||
| SRR13003977_1.fastq.gz | Fastqsanger.gz | |||
| SRR13003977_2.fastq.gz | Fastqsanger.gz | |||
| SRR13003978_1.fastq.gz | Fastqsanger.gz |
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Project description:Relapse is one of the biggest challenges in treating acute myeloid leukemia (AML) due to leukemia stem cells (LSCs) resisting chemotherapy, providing a cellular reservoir to form the basis for relapse. Here, we identify CaMK2D is a critical regulator of stemness and leukemogenesis of AML. Transcriptionally, loss of CaMK2D was associated with down-regulation kinds of metabolic pathway of AML.
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Project description:Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy. HL-60, MOLM-14, and U937 cell lines were transduced in triplicate with a control luciferase-directed shRNA (target sequence CCTAAGGTTAAGTCGCCCTCG), and in duplicate with two SYK-directed shRNAs: shSYK_1 (clone ID TRCN0000197257, target sequence GCAGCAGAACAGACATGTCAA) and shSYK_2 (clone ID TRCN0000003163 , target sequence GCAGGCCATCATCAGTCAGAA), and were then selected with 1 µg/ml puromycin 48 hours post-infection. At day 5 post-infection, RNA was extracted and profiled using HT HG-U133A arrays (Affymetrix) at the Broad Institute (Cambridge, MA, USA). The computational analysis of the gene expression data was performed through the Genome Space bioinformatics platform (http://www.genomespace.org).
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