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JOURNAL ARTICLE
Jennifer LoCasale-Crouch, Margaret Kathleen Wallace, Timothy Heeren, Stephen Kerr, Yitong Yue, Genevieve Deeken, Khara Turnbull, Brianna Jaworski, Mayaris Cubides Mateus, Rachel Moon, Fern Robin Hauck, Ann Kellams, Eve Colson, Michael Jay Corwin
BACKGROUND: Breastfeeding has long-lasting effects on children's cognition, behavioral, mental and physical health. Previous research shows parental characteristics (e.g., education, race/ethnicity, income level) are associated with breastfeeding initiation and duration. Further, research shows significant variation in access to community resources by race/ethnicity. It is unclear how community resources may impact breastfeeding practices and how this might intersect with maternal race/ethnicity...
March 6, 2024: International Breastfeeding Journal
#2
JOURNAL ARTICLE
David K Miyamoto, Nicole M Curnutt, Sun-Mi Park, Alexios Stavropoulos, Michael G Kharas, Christina M Woo
Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35 ...
December 12, 2023: Journal of Medicinal Chemistry
#3
JOURNAL ARTICLE
Hanzhi Luo, Mariela Cortés-López, Cyrus L Tam, Michael Xiao, Isaac Wakiro, Karen L Chu, Aspen Pierson, Mandy Chan, Kathryn Chang, Xuejing Yang, Daniel Fecko, Grace Han, Eun-Young Erin Ahn, Quaid D Morris, Dan A Landau, Michael G Kharas
Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. m6 A RNA methylation controls symmetric commitment and inflammation of hematopoietic stem cells (HSCs) through unknown mechanisms. Here, we demonstrate that the nuclear speckle protein SON is an essential m6 A target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of m6 A identified that m6 A mRNA methylation of Son increases during HSC commitment...
December 7, 2023: Cell Stem Cell
#4
Vianne R Gao, Rui Yang, Arnav Das, Renhe Luo, Hanzhi Luo, Dylan R McNally, Ioannis Karagiannidis, Martin A Rivas, Zhong-Min Wang, Darko Barisic, Alireza Karbalayghareh, Wilfred Wong, Yingqian A Zhan, Christopher R Chin, William Noble, Jeff A Bilmes, Effie Apostolou, Michael G Kharas, Wendy Béguelin, Aaron D Viny, Danwei Huangfu, Alexander Y Rudensky, Ari M Melnick, Christina S Leslie
The identification of cell-type-specific 3D chromatin interactions between regulatory elements can help to decipher gene regulation and to interpret the function of disease-associated non-coding variants. However, current chromosome conformation capture (3C) technologies are unable to resolve interactions at this resolution when only small numbers of cells are available as input. We therefore present ChromaFold, a deep learning model that predicts 3D contact maps and regulatory interactions from single-cell ATAC sequencing (scATAC-seq) data alone...
July 28, 2023: bioRxiv
#5
JOURNAL ARTICLE
Florisela Herrejon Chavez, Hanzhi Luo, Paolo Cifani, Alli Pine, Karen L Chu, Suhasini Joshi, Ersilia Barin, Alexandra Schurer, Mandy Chan, Kathryn Chang, Grace Y Q Han, Aspen J Pierson, Michael Xiao, Xuejing Yang, Lindsey M Kuehm, Yuning Hong, Diu T T Nguyen, Gabriela Chiosis, Alex Kentsis, Christina Leslie, Ly P Vu, Michael G Kharas
Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance...
April 21, 2023: Nature Communications
#6
JOURNAL ARTICLE
Andriana G Kotini, Saul Carcamo, Nataly Cruz-Rodriguez, Malgorzata Olszewska, Tiansu Wang, Deniz Demircioglu, Chan-Jung Chang, Elsa Bernard, Mark P Chao, Ravindra Majeti, Hanzhi Luo, Michael G Kharas, Dan Hasson, Eirini P Papapetrou
UNLABELLED: The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features...
April 17, 2023: Blood cancer discovery
#7
JOURNAL ARTICLE
Sun-Mi Park, David K Miyamoto, Grace Y Q Han, Mandy Chan, Nicole M Curnutt, Nathan L Tran, Anthony Velleca, Jun Hyun Kim, Alexandra Schurer, Kathryn Chang, Wenqing Xu, Michael G Kharas, Christina M Woo
Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay...
April 10, 2023: Cancer Cell
#8
JOURNAL ARTICLE
Coraline Mlynarczyk, Matt Teater, Juhee Pae, Christopher R Chin, Ling Wang, Theinmozhi Arulraj, Darko Barisic, Antonin Papin, Kenneth B Hoehn, Ekaterina Kots, Jonatan Ersching, Arnab Bandyopadhyay, Ersilia Barin, Hui Xian Poh, Chiara M Evans, Amy Chadburn, Zhengming Chen, Hao Shen, Hannah M Isles, Benedikt Pelzer, Ioanna Tsialta, Ashley S Doane, Huimin Geng, Muhammad Hassan Rehman, Jonah Melnick, Wyatt Morgan, Diu T T Nguyen, Olivier Elemento, Michael G Kharas, Samie R Jaffrey, David W Scott, George Khelashvili, Michael Meyer-Hermann, Gabriel D Victora, Ari Melnick
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts...
January 20, 2023: Science
#9
JOURNAL ARTICLE
Tatiana Erazo, Chiara M Evans, Daniel Zakheim, Karen L Chu, Alice Yunsi Refermat, Zahra Asgari, Xuejing Yang, Mariana Da Silva Ferreira, Sanjoy Mehta, Marco Vincenzo Russo, Andrea Knezevic, Xi-Ping Zhang, Zhengming Chen, Myles Fennell, Ralph Garippa, Venkatraman Seshan, Elisa de Stanchina, Olena Barbash, Connie Lee Batlevi, Christina S Leslie, Ari M Melnick, Anas Younes, Michael G Kharas
To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth...
September 27, 2022: Nature Communications
#10
JOURNAL ARTICLE
Martin G Klatt, Tao Dao, Zhiyuan Yang, Jianying Liu, Sung Soo Mun, Megan M Dacek, Hanzhi Luo, Thomas J Gardner, Christopher Bourne, Leila Peraro, Zita E H Aretz, Tanya Korontsvit, Michael Lau, Michael G Kharas, Cheng Liu, David A Scheinberg
Target identification for chimeric antigen receptor (CAR) T-cell therapies remains challenging due to the limited repertoire of tumor-specific surface proteins. Intracellular proteins presented in the context of cell surface HLA provide a wide pool of potential antigens targetable through T-cell receptor mimic antibodies. Mass spectrometry (MS) of HLA ligands from 8 hematologic and nonhematologic cancer cell lines identified a shared, non-immunogenic, HLA-A*02-restricted ligand (ALNEQIARL) derived from the kinetochore-associated NDC80 gene...
August 25, 2022: Blood
#11
JOURNAL ARTICLE
Hanzhi Luo, Michael G Kharas
No abstract text is available yet for this article.
August 1, 2022: Haematologica
#12
JOURNAL ARTICLE
Ying Wang, Frederick S Yen, Xiphias Ge Zhu, Rebecca C Timson, Ross Weber, Changrui Xing, Yuyang Liu, Benjamin Allwein, Hanzhi Luo, Hsi-Wen Yeh, Søren Heissel, Gokhan Unlu, Eric R Gamazon, Michael G Kharas, Richard Hite, Kıvanç Birsoy
Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism1 . Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions2 . GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria...
November 2021: Nature
#13
JOURNAL ARTICLE
Camila Prieto, Diu T T Nguyen, Zhaoqi Liu, Justin Wheat, Alexendar Perez, Saroj Gourkanti, Timothy Chou, Ersilia Barin, Anthony Velleca, Thomas Rohwetter, Arthur Chow, James Taggart, Angela M Savino, Katerina Hoskova, Meera Dhodapkar, Alexandra Schurer, Trevor S Barlowe, Ly P Vu, Christina Leslie, Ulrich Steidl, Raul Rabadan, Michael G Kharas
RNA binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be found dysregulated in hematological malignancies. Here, we identify the RBP RBMX and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX/L1 are overexpressed in acute myeloid leukemia (AML) primary patients compared to healthy individuals, and RBMX/L1 loss delayed leukemia development. RBMX/L1 loss lead to significant changes in chromatin accessibility, as well as chromosomal breaks and gaps...
July 2021: Nature Cancer
#14
JOURNAL ARTICLE
Yuanming Cheng, Wei Xie, Brian F Pickering, Karen L Chu, Angela M Savino, Xuejing Yang, Hanzhi Luo, Diu Tt Nguyen, Shanlan Mo, Ersilia Barin, Anthony Velleca, Thomas M Rohwetter, Dinshaw J Patel, Samie R Jaffrey, Michael G Kharas
N6 -Methyladenosine (m6 A) on mRNAs mediates different biological processes and its dysregulation contributes to tumorigenesis. How m6 A dictates its diverse molecular and cellular effects in leukemias remains unknown. We found that YTHDC1 is the essential m6 A reader in myeloid leukemia from a genome-wide CRISPR screen and that m6 A is required for YTHDC1 to undergo liquid-liquid phase separation and form nuclear YTHDC1-m6 A condensates (nYACs). The number of nYACs increases in acute myeloid leukemia (AML) cells compared with normal hematopoietic stem and progenitor cells...
July 12, 2021: Cancer Cell
#15
Laura K Donovan, Alberto Delaidelli, Sujith K Joseph, Kevin Bielamowicz, Kristen Fousek, Borja L Holgado, Alex Manno, Dilakshan Srikanthan, Ahmed Z Gad, Randy Van Ommeren, David Przelicki, Cory Richman, Vijay Ramaswamy, Craig Daniels, Jonelle G Pallota, Tajana Douglas, Alyssa C M Joynt, Joonas Haapasalo, Carolina Nor, Maria C Vladoiu, Claudia M Kuzan-Fischer, Livia Garzia, Stephen C Mack, Srinidhi Varadharajan, Matthew L Baker, Liam Hendrikse, Michelle Ly, Kaitlin Kharas, Polina Balin, Xiaochong Wu, Lei Qin, Ning Huang, Ana Guerreiro Stucklin, A Sorana Morrissy, Florence M G Cavalli, Betty Luu, Raul Suarez, Pasqualino De Antonellis, Antony Michealraj, Avesta Rastan, Meenakshi Hegde, Martin Komosa, Olga Sirbu, Sachin A Kumar, Zied Abdullaev, Claudia C Faria, Stephen Yip, Juliette Hukin, Uri Tabori, Cynthia Hawkins, Ken Aldape, Mads Daugaard, John M Maris, Poul H Sorensen, Nabil Ahmed, Michael D Taylor
No abstract text is available yet for this article.
June 2021: Nature Medicine
#16
JOURNAL ARTICLE
Veronica Granatiero, Nicole M Sayles, Angela M Savino, Csaba Konrad, Michael G Kharas, Hibiki Kawamata, Giovanni Manfredi
ALS (amyotrophic lateral sclerosis), the most common motor neuron disease, causes muscle denervation and rapidly fatal paralysis. While motor neurons are the most affected cells in ALS, studies on the pathophysiology of the disease have highlighted the importance of non-cell autonomous mechanisms, which implicate astrocytes and other glial cells. In ALS, subsets of reactive astrocytes lose their physiological functions and become toxic for motor neurons, thereby contributing to disease pathogenesis. Evidence of astrocyte contribution to disease pathogenesis are well established in cellular and animal models of familial ALS linked to mutant SOD1, where astrocytes promote motor neuron cell death...
December 2021: Autophagy
#17
JOURNAL ARTICLE
Melody Allensworth-James, Jewel Banik, Angela Odle, Linda Hardy, Alex Lagasse, Ana Rita Silva Moreira, Jordan Bird, Christian L Thomas, Nathan Avaritt, Michael G Kharas, Christopher J Lengner, Stephanie D Byrum, Melanie C MacNicol, Gwen V Childs, Angus M MacNicol
The adipokine leptin regulates energy homeostasis through ubiquitously expressed leptin receptors. Leptin has a number of major signaling targets in the brain, including cells of the anterior pituitary (AP). We have previously reported that mice lacking leptin receptors in AP somatotropes display growth hormone (GH) deficiency, metabolic dysfunction, and adult-onset obesity. Among other targets, leptin signaling promotes increased levels of the pituitary transcription factor POU1F1, which in turn regulates the specification of somatotrope, lactotrope, and thyrotrope cell lineages within the AP...
March 1, 2021: Endocrinology
#18
JOURNAL ARTICLE
Sumiko Takao, Lauren Forbes, Masahiro Uni, Shuyuan Cheng, Jose Mario Bello Pineda, Yusuke Tarumoto, Paolo Cifani, Gerard Minuesa, Celine Chen, Michael G Kharas, Robert K Bradley, Christopher R Vakoc, Richard P Koche, Alex Kentsis
Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1...
February 2, 2021: ELife
#19
JOURNAL ARTICLE
Melody Allensworth-James, Jewel Banik, Angela Odle, Linda Hardy, Alex Lagasse, Ana Rita Silva Moreira, Jordan Bird, Christian L Thomas, Nathan Avaritt, Michael G Kharas, Christopher J Lengner, Stephanie D Byrum, Melanie C MacNicol, Gwen V Childs, Angus M MacNicol
The adipokine leptin regulates energy homeostasis through ubiquitously expressed leptin receptors. Leptin has a number of major signaling targets in the brain, including cells of the anterior pituitary (AP). We have previously reported that mice lacking leptin receptors in AP somatotropes display growth hormone (GH) deficiency, metabolic dysfunction, and adult-onset obesity. Among other targets, leptin signaling promotes increased levels of the pituitary transcription factor POU1F1, which in turn regulates the specification of somatotrope, lactotrope, and thyrotrope cell lineages within the AP...
March 1, 2021: Endocrinology
#20
JOURNAL ARTICLE
Florencia Palacios, Xiao-Jie Yan, Gerardo Ferrer, Shih-Shih Chen, Stefano Vergani, Xuejing Yang, Jeffrey Gardner, Jaqueline C Barrientos, Philip Rock, Richard Burack, Jonathan E Kolitz, Steven L Allen, Michael G Kharas, Omar Abdel-Wahab, Kanti R Rai, Nicholas Chiorazzi
Progression of chronic lymphocytic leukemia (CLL) results from the expansion of a small fraction of proliferating leukemic B cells. When comparing the global gene expression of recently divided CLL cells with that of previously divided cells, we found higher levels of genes involved in regulating gene expression. One of these was the oncogene Musashi 2 (MSI2), an RNA-binding protein that induces or represses translation. While there is an established role for MSI2 in normal and malignant stem cells, much less is known about its expression and role in CLL...
January 27, 2021: Leukemia
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