Publications by authors named "Michelle Ki"

10 Publications

  • Page 1 of 1

Computerized Surgical Planning in Mandibular Reconstruction: Barriers to Implementation and Cost-Saving Initiatives.

J Craniofac Surg 2021 Mar 22. Epub 2021 Mar 22.

Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY.

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http://dx.doi.org/10.1097/SCS.0000000000007625DOI Listing
March 2021

The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim-Chester Disease.

Cancers (Basel) 2020 Nov 3;12(11). Epub 2020 Nov 3.

Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel.

The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.
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http://dx.doi.org/10.3390/cancers12113240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693724PMC
November 2020

Mutant SF3B1 promotes AKT- and NF-κB-driven mammary tumorigenesis.

J Clin Invest 2021 Jan;131(1)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-κB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3' splice sites (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.
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http://dx.doi.org/10.1172/JCI138315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773370PMC
January 2021

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Nat Genet 2020 04 23;52(4):378-387. Epub 2020 Mar 23.

New York Genome Center, New York, NY, USA.

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies and clonal hematopoiesis. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.
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http://dx.doi.org/10.1038/s41588-020-0595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216752PMC
April 2020

Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization.

Cancer Discov 2020 Jun 18;10(6):806-821. Epub 2020 Mar 18.

Program for Mathematical Genomics, Columbia University, New York, New York.

Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring hotspot mutations, identifying hundreds of cryptic 3' splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common mutation activates MYC via effects conserved across human and mouse cells. mutations promote decay of transcripts encoding the protein phosphatase 2A (PP2A) subunit PPP2R5A, increasing MYC S62 and BCL2 S70 phosphorylation which, in turn, promotes MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis, elucidating a therapeutic approach to aberrant splicing by mutant SF3B1. SIGNIFICANCE: Here, we identify that mutations in , the most commonly mutated splicing factor gene across cancers, alter splicing of a specific subunit of the PP2A serine/threonine phosphatase complex to confer post-translational MYC and BCL2 activation, which is therapeutically intervenable using an FDA-approved drug...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1330DOI Listing
June 2020

Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms.

Nat Med 2019 12 25;25(12):1839-1842. Epub 2019 Nov 25.

Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.
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http://dx.doi.org/10.1038/s41591-019-0653-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898787PMC
December 2019

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

Cancer Cell 2019 08;36(2):194-209.e9

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacological Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.
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http://dx.doi.org/10.1016/j.ccell.2019.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194031PMC
August 2019

Efficacy of MEK inhibition in patients with histiocytic neoplasms.

Nature 2019 03 13;567(7749):521-524. Epub 2019 Mar 13.

Weill Cornell Medical College, New York, NY, USA.

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway. For the 50% of patients with histiocytosis who have BRAF mutations, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease. However, no standard therapy exists for the remaining 50% of patients who lack BRAF mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAF mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.
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http://dx.doi.org/10.1038/s41586-019-1012-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438729PMC
March 2019

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.

Cancer Cell 2019 03 21;35(3):369-384.e7. Epub 2019 Feb 21.

Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.
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http://dx.doi.org/10.1016/j.ccell.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424627PMC
March 2019

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations.

Cancer Cell 2018 08;34(2):225-241.e8

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Zuckerman 701, 408 East 69(th) Street, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.
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http://dx.doi.org/10.1016/j.ccell.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373472PMC
August 2018