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- Vu, Ly P., et al.
(författare)
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Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:6, s. 866-875
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Tidskriftsartikel (refereegranskat)abstract
- The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis. Gene expression profiling of SYNCRIP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program. SYNCRIP and MSI2 interact indirectly though shared mRNA targets. SYNCRIP maintains HOXA9 translation, and MSI2 or HOXA9 overexpression rescued the effects of SYNCRIP depletion. Altogether, our data identify SYNCRIP as a new RBP that controls the myeloid leukemia stem cell program. We propose that targeting these RBP complexes might provide a novel therapeutic strategy in leukemia.
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- Lee, S. W., et al.
(författare)
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Sol-gel integrated protein microarray for high-resolution signal readout of psa (prostate specific antigen) in clinical samples
- 2010
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Ingår i: 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2010, MicroTAS 2010. - 9781618390622 ; 2, s. 800-802
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Konferensbidrag (refereegranskat)abstract
- In this study, we demonstrate a new protein microarray technology for highly sensitive detection of PSA (prostate caser specific antigen) in scrum samples. Using the optically active sol-gel nanocomposites, which can hold capturing probes in native and surface morphology tailored porous silicon, purified PSA (Prostate Specific Antigen) in human female serum was assessed by FlTC-antiPSA in broad dynamic range of the sandwich (1 pg/mL to Ing/mL). Additionally, we tested reverse phase assay using our developed system, which purified PSA imbedded in sol-gel and FITC labeled its counter antibody was accessed. Dynamic range was 60 fg/mL to 6ng/mL. Our concept can allow the measurement oflow amount of PSA at pg/ml range and thus, it is possible to do relative quantification for marker protein as well.
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- Puram, Rishi V, et al.
(författare)
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Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML
- 2016
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 165:2, s. 16-303
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Tidskriftsartikel (refereegranskat)abstract
- Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.
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- Järås, Marcus, et al.
(författare)
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Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
- 2014
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 211:4, s. 605-612
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Tidskriftsartikel (refereegranskat)abstract
- Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 alpha (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
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