Publications by authors named "Cara Lunn Shirai"

7 Publications

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Corrigendum to "Haploinsufficiency of multiple del(5q) genes induce B cell abnormalities in mice" [Leuk. Res. 96C (2020) 106428].

Leuk Res 2021 Jan 4;100:106478. Epub 2020 Dec 4.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106478DOI Listing
January 2021

Haploinsufficiency of multiple del(5q) genes induce B cell abnormalities in mice.

Leuk Res 2020 09 23;96:106428. Epub 2020 Jul 23.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, United States; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768807PMC
September 2020

Sequencing-Based Measurable Residual Disease Testing in Acute Myeloid Leukemia.

Front Cell Dev Biol 2020 8;8:249. Epub 2020 May 8.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States.

Next generation sequencing (NGS) methods have allowed for unprecedented genomic characterization of acute myeloid leukemia (AML) over the last several years. Further advances in NGS-based methods including error correction using unique molecular identifiers (UMIs) have more recently enabled the use of NGS-based measurable residual disease (MRD) detection. This review focuses on the use of NGS-based MRD detection in AML, including basic methodologies and clinical applications.
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http://dx.doi.org/10.3389/fcell.2020.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225302PMC
May 2020

Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

PLoS One 2017 8;12(2):e0170470. Epub 2017 Feb 8.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170470PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298293PMC
August 2017

Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome.

Nat Commun 2017 01 9;8:14060. Epub 2017 Jan 9.

Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations-drug and mutation-compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins.
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http://dx.doi.org/10.1038/ncomms14060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227701PMC
January 2017

Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.

Cancer Cell 2015 May;27(5):631-43

Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA. Electronic address:

Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.
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http://dx.doi.org/10.1016/j.ccell.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430854PMC
May 2015