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Article ; Online: Drug Resistant Melanoma May Be Vulnerable to Inhibitors of Serine Synthesis.

Doepner, Miriam / Lee, In Young / Ridky, Todd W

The Journal of investigative dermatology

2020 Volume 140, Issue 11, Page(s) 2114–2116

Abstract: NRAS-driven melanomas frequently develop resistance to MAPK/extracellular signal-regulated kinase kinase inhibitors (MEKis), which limits their therapeutic utility. Nguyen et al. (2020) show that MEKi-resistant cells upregulate phosphoglycerate ... ...

Abstract	NRAS-driven melanomas frequently develop resistance to MAPK/extracellular signal-regulated kinase kinase inhibitors (MEKis), which limits their therapeutic utility. Nguyen et al. (2020) show that MEKi-resistant cells upregulate phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine synthesis. Suppression of PHGDH rendered cells sensitive to MEKis, suggesting that PHGDH may be a therapeutic target for melanoma.
MeSH term(s)	GTP Phosphohydrolases ; Glutathione ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Membrane Proteins ; Mitogen-Activated Protein Kinase Kinases ; Pharmaceutical Preparations ; Phosphoglycerate Dehydrogenase/genetics ; Phosphoglycerate Dehydrogenase/metabolism ; Serine/metabolism ; Up-Regulation
Chemical Substances	Membrane Proteins ; Pharmaceutical Preparations ; Serine (452VLY9402) ; Phosphoglycerate Dehydrogenase (EC 1.1.1.95) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2020.05.103
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Article ; Online: Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression.

Kohli, Jaskaren / Ge, Chen / Fitsiou, Eleni / Doepner, Miriam / Brandenburg, Simone M / Faller, William J / Ridky, Todd W / Demaria, Marco

Nature communications

2022 Volume 13, Issue 1, Page(s) 7923

Abstract: Human melanocytic nevi (moles) result from a brief period of clonal expansion of melanocytes. As a cellular defensive mechanism against oncogene-induced hyperplasia, nevus-resident melanocytes enter a senescent state of stable cell cycle arrest. ... ...

Abstract	Human melanocytic nevi (moles) result from a brief period of clonal expansion of melanocytes. As a cellular defensive mechanism against oncogene-induced hyperplasia, nevus-resident melanocytes enter a senescent state of stable cell cycle arrest. Senescent melanocytes can persist for months in mice and years in humans with a risk to escape the senescent state and progress to melanoma. The mechanisms providing prolonged survival of senescent melanocytes remain poorly understood. Here, we show that senescent melanocytes in culture and in nevi express high level of the anti-apoptotic BCL-2 family member BCL-W but remain insensitive to the pan-BCL-2 inhibitor ABT-263. We demonstrate that resistance to ABT-263 is driven by mTOR-mediated enhanced translation of another anti-apoptotic member, MCL-1. Strikingly, the combination of ABT-263 and MCL-1 inhibitors results in synthetic lethality to senescent melanocytes, and its topical application sufficient to eliminate nevi in male mice. These data highlight the important role of redundant anti-apoptotic mechanisms for the survival advantage of senescent melanocytes, and the proof-of-concept for a non-invasive combination therapy for nevi removal.
MeSH term(s)	Male ; Humans ; Animals ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Melanocytes/metabolism ; Nevus/metabolism ; Nevus, Pigmented ; Skin Neoplasms/metabolism
Chemical Substances	navitoclax (XKJ5VVK2WD) ; Myeloid Cell Leukemia Sequence 1 Protein
Language	English
Publishing date	2022-12-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-35657-9
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Article ; Online: LNS8801 inhibits Acute Myeloid Leukemia by Inducing the Production of Reactive Oxygen Species and Activating the Endoplasmic Reticulum Stress Pathway.

Lee, Inyoung / Doepner, Miriam / Weissenrieder, Jillian / Majer, Ariana D / Mercado, Sophia / Estell, Angela / Natale, Christopher A / Sung, Pamela J / Foskett, J Kevin / Carroll, Martin P / Ridky, Todd W

Cancer research communications

2023 Volume 3, Issue 8, Page(s) 1594–1606

Abstract: Despite recent therapeutic advances, the 5-year survival rate for adults with acute myeloid leukemia (AML) is poor and standard-of-care chemotherapy is associated with significant toxicity, highlighting the need for new therapeutic approaches. Recent ... ...

Abstract	Despite recent therapeutic advances, the 5-year survival rate for adults with acute myeloid leukemia (AML) is poor and standard-of-care chemotherapy is associated with significant toxicity, highlighting the need for new therapeutic approaches. Recent work from our group and others established that the G protein-coupled estrogen receptor (GPER) is tumor suppressive in melanoma and other solid tumors. We performed a preliminary screen of human cancer cell lines from multiple malignancies and found that LNS8801, a synthetic pharmacologic agonist of GPER currently in early phase clinical trials, promoted apoptosis in human AML cells. Using human AML cell lines and primary cells, we show that LNS8801 inhibits human AML in preclinical Significance: Previous work demonstrated that LNS8801 inhibits cancer via GPER activation, especially in solid tumors. Here we show that LNS8801 inhibits AML via GPER-independent mechanisms that include ROS induction and ER activation.
MeSH term(s)	Adult ; Humans ; Reactive Oxygen Species ; Endoribonucleases ; Protein Serine-Threonine Kinases ; Leukemia, Myeloid, Acute/drug therapy ; Estrogens ; Endoplasmic Reticulum Stress
Chemical Substances	Reactive Oxygen Species ; Endoribonucleases (EC 3.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Estrogens
Language	English
Publishing date	2023-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-22-0478
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Article ; Online: Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling.

Doepner, Miriam / Lee, Inyoung / Natale, Christopher A / Brathwaite, Roderick / Venkat, Swati / Kim, Sung Hoon / Wei, Yiliang / Vakoc, Christopher R / Capell, Brian C / Katzenellenbogen, John A / Katzenellenbogen, Benita S / Feigin, Michael E / Ridky, Todd W

Science advances

2022 Volume 8, Issue 35, Page(s) eabn4007

Abstract: Melanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic ... ...

Abstract	Melanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity and susceptibility to malignant transformation, independent of melanin and ultraviolet exposure. These differences result from dihydroxyphenylalanine (DOPA), a melanin precursor synthesized at higher levels in melanocytes from darkly pigmented skin. We used both high-throughput pharmacologic and genetic in vivo CRISPR screens to determine that DOPA limits melanocyte and melanoma cell proliferation by inhibiting the muscarinic acetylcholine receptor M
Language	English
Publishing date	2022-09-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abn4007
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Article ; Online: Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer.

Sela, Yogev / Li, Jinyang / Maheswaran, Shivahamy / Norgard, Robert / Yuan, Salina / Hubbi, Maimon / Doepner, Miriam / Xu, Jimmy P / Ho, Elaine S / Mesaros, Clementina / Sheehan, Colin / Croley, Grace / Muir, Alexander / Blair, Ian A / Shalem, Ophir / Dang, Chi V / Stanger, Ben Z

Cancer research

2022 Volume 82, Issue 10, Page(s) 1890–1908

Abstract: Solid tumors possess heterogeneous metabolic microenvironments where oxygen and nutrient availability are plentiful (fertile regions) or scarce (arid regions). While cancer cells residing in fertile regions proliferate rapidly, most cancer cells in vivo ... ...

Abstract	Solid tumors possess heterogeneous metabolic microenvironments where oxygen and nutrient availability are plentiful (fertile regions) or scarce (arid regions). While cancer cells residing in fertile regions proliferate rapidly, most cancer cells in vivo reside in arid regions and exhibit a slow-cycling state that renders them chemoresistant. Here, we developed an in vitro system enabling systematic comparison between these populations via transcriptome analysis, metabolomic profiling, and whole-genome CRISPR screening. Metabolic deprivation led to pronounced transcriptional and metabolic reprogramming, resulting in decreased anabolic activities and distinct vulnerabilities. Reductions in anabolic, energy-consuming activities, particularly cell proliferation, were not simply byproducts of the metabolic challenge, but rather essential adaptations. Mechanistically, Bcl-xL played a central role in the adaptation to nutrient and oxygen deprivation. In this setting, Bcl-xL protected quiescent cells from the lethal effects of cell-cycle entry in the absence of adequate nutrients. Moreover, inhibition of Bcl-xL combined with traditional chemotherapy had a synergistic antitumor effect that targeted cycling cells. Bcl-xL expression was strongly associated with poor patient survival despite being confined to the slow-cycling fraction of human pancreatic cancer cells. These findings provide a rationale for combining traditional cancer therapies that target rapidly cycling cells with those that target quiescent, chemoresistant cells associated with nutrient and oxygen deprivation. Significance: The majority of pancreatic cancer cells inhabit nutrient- and oxygen-poor tumor regions and require Bcl-xL for their survival, providing a compelling antitumor metabolic strategy.
MeSH term(s)	Apoptosis ; Cell Cycle ; Cell Line, Tumor ; Humans ; Nutrients ; Oxygen/metabolism ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Tumor Microenvironment ; bcl-X Protein/metabolism
Chemical Substances	BCL2L1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; bcl-X Protein ; Oxygen (S88TT14065)
Language	English
Publishing date	2022-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-0431
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Article ; Online: The BRISC deubiquitinating enzyme complex limits hematopoietic stem cell expansion by regulating JAK2 K63-ubiquitination.

Donaghy, Ryan / Han, Xu / Rozenova, Krasimira / Lv, Kaosheng / Jiang, Qinqin / Doepner, Miriam / Greenberg, Roger A / Tong, Wei

Blood

2019 Volume 133, Issue 14, Page(s) 1560–1571

Abstract: Hematopoietic stem cell (HSC) homeostasis is controlled by cytokine receptor-mediated Janus kinase 2 (JAK2) signaling. We previously found that JAK2 is promptly ubiquitinated upon cytokine stimulation. Whether a competing JAK2 deubiquitination activity ... ...

Abstract	Hematopoietic stem cell (HSC) homeostasis is controlled by cytokine receptor-mediated Janus kinase 2 (JAK2) signaling. We previously found that JAK2 is promptly ubiquitinated upon cytokine stimulation. Whether a competing JAK2 deubiquitination activity exists is unknown. LNK is an essential adaptor protein that constrains HSC expansion through dampening thrombopoietin (TPO)-induced JAK2 signaling. We show here that a LNK-associated lysine-63 (K63)-deubiquitinating enzyme complex, Brcc36 isopeptidase complex (BRISC), attenuates HSC expansion through control of JAK2 signaling. We pinpoint a direct interaction between the LNK SH2 domain and a phosphorylated tyrosine residue in KIAA0157 (Abraxas2), a unique and defining BRISC component.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cell Proliferation ; Deubiquitinating Enzymes/genetics ; Deubiquitinating Enzymes/physiology ; Hematopoietic Stem Cells/cytology ; Humans ; Janus Kinase 2/metabolism ; Mice ; Nuclear Matrix-Associated Proteins/metabolism ; Receptors, Thrombopoietin/metabolism ; Signal Transduction ; Thrombopoietin/pharmacology ; Ubiquitin-Specific Proteases/metabolism ; Ubiquitination ; src Homology Domains
Chemical Substances	ABRAXAS2 protein, human ; Adaptor Proteins, Signal Transducing ; Nuclear Matrix-Associated Proteins ; Receptors, Thrombopoietin ; SH2B3 protein, human ; Thrombopoietin (9014-42-0) ; JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2) ; BRCC3 protein, human (EC 3.4.19.12) ; Deubiquitinating Enzymes (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12)
Language	English
Publishing date	2019-02-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2018-10-877563
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Article ; Online: LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors.

Egolf, Shaun / Aubert, Yann / Doepner, Miriam / Anderson, Amy / Maldonado-Lopez, Alexandra / Pacella, Gina / Lee, Jessica / Ko, Eun Kyung / Zou, Jonathan / Lan, Yemin / Simpson, Cory L / Ridky, Todd / Capell, Brian C

Cell reports

2019 Volume 28, Issue 8, Page(s) 1981–1992.e7

Abstract: Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold ... ...

Abstract	Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1's role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.
MeSH term(s)	3T3 Cells ; Adult ; Animals ; Binding Sites ; Carcinoma, Squamous Cell/pathology ; Cell Differentiation/genetics ; Cell Line, Tumor ; Cell Lineage/genetics ; Epidermis/metabolism ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Gene Expression Regulation ; Genome, Human ; Histone Demethylases/antagonists & inhibitors ; Histone Demethylases/metabolism ; Histones/metabolism ; Humans ; Lysine/metabolism ; Methylation ; Mice ; Protein Binding ; Snail Family Transcription Factors/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic
Chemical Substances	Histones ; SNAI2 protein, human ; Snail Family Transcription Factors ; Transcription Factors ; Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2019-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.07.058
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Article: Disruption of the menin-MLL interaction triggers menin protein degradation via ubiquitin-proteasome pathway.

Wu, Yuan / Doepner, Miriam / Hojnacki, Taylor / Feng, Zijie / Katona, Bryson W / He, Xin / Ma, Jian / Cao, Yan / Busino, Luca / Zhou, Fuxiang / Hua, Xianxin

American journal of cancer research

2019 Volume 9, Issue 8, Page(s) 1682–1694

Abstract: Menin, a protein encoded by ... ...

Abstract	Menin, a protein encoded by the
Language	English
Publishing date	2019-08-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2589522-9
ISSN	2156-6976
ISSN	2156-6976
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Article ; Online: Somatic structural variation targets neurodevelopmental genes and identifies

Lopez, Gonzalo / Conkrite, Karina L / Doepner, Miriam / Rathi, Komal S / Modi, Apexa / Vaksman, Zalman / Farra, Lance M / Hyson, Eric / Noureddine, Moataz / Wei, Jun S / Smith, Malcolm A / Asgharzadeh, Shahab / Seeger, Robert C / Khan, Javed / Auvil, Jaime Guidry / Gerhard, Daniela S / Maris, John M / Diskin, Sharon J

Genome research

2020 Volume 30, Issue 9, Page(s) 1228–1242

Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma shows a relative paucity of somatic single-nucleotide variants (SNVs) and small ... ...

Abstract	Neuroblastoma is a malignancy of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Like many childhood cancers, neuroblastoma shows a relative paucity of somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) compared to adult cancers. Here, we assessed the contribution of somatic structural variation (SV) in neuroblastoma using a combination of whole-genome sequencing (WGS) of tumor-normal pairs (
MeSH term(s)	Cell Line, Tumor ; Chromothripsis ; Cohort Studies ; DNA Breaks ; DNA Copy Number Variations ; Female ; Genes, Tumor Suppressor ; Genomic Structural Variation ; Humans ; Male ; N-Myc Proto-Oncogene Protein/genetics ; Nerve Tissue Proteins/genetics ; Neuroblastoma/genetics ; Neuroblastoma/pathology ; Neurogenesis/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; RNA, Neoplasm ; RNA-Seq ; Risk Assessment ; Telomerase/genetics ; Tumor Cells, Cultured ; Whole Genome Sequencing
Chemical Substances	MYCN protein, human ; N-Myc Proto-Oncogene Protein ; Nerve Tissue Proteins ; RNA, Neoplasm ; SHANK2 protein, human ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2020-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.252106.119
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