Activation of GPR44 Decreases Severity of Myeloid Leukemia Via Specific Targeting of Leukemia Initiating Stem Cells

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Jul 17

PMID 37459233

Authors

Fenghua Qian

Shaneice K Nettleford

Jiayan Zhou

Brooke E Arner

Molly A Hall

Arati Sharma

Charyguly Annageldiyev

Randy M Rossi

Diwakar B Tukaramrao

Deborpita Sarkar

Shailaja Hegde

Ujjawal H Gandhi

Emily R Finch

Laura Goodfield

Michael D Quickel

David F Claxton

Robert F Paulson

K Sandeep Prabhu

Affiliations

Soon will be listed here.

Abstract

Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ-PGJ, and 15d-PGJ, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44 LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.

Citing Articles

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References

Bie Q, Zhang P, Su Z, Zheng D, Ying X, Wu Y . Polarization of ILC2s in peripheral blood might contribute to immunosuppressive microenvironment in patients with gastric cancer. J Immunol Res. 2014; 2014:923135. PMC: 3987940. DOI: 10.1155/2014/923135. View

De Kouchkovsky I, Abdul-Hay M . 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J. 2016; 6(7):e441. PMC: 5030376. DOI: 10.1038/bcj.2016.50. View

Liu Q, Chen L, Atkinson J, Claxton D, Wang H . Atg5-dependent autophagy contributes to the development of acute myeloid leukemia in an MLL-AF9-driven mouse model. Cell Death Dis. 2016; 7(9):e2361. PMC: 5059867. DOI: 10.1038/cddis.2016.264. View

Kasaikina M, Kravtsova M, Lee B, Seravalli J, Peterson D, Walter J . Dietary selenium affects host selenoproteome expression by influencing the gut microbiota. FASEB J. 2011; 25(7):2492-9. PMC: 3114522. DOI: 10.1096/fj.11-181990. View

Yenerall P, Kollipara R, Avila K, Peyton M, Eide C, Bottomly D . Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations. Cancer Res. 2021; 81(18):4685-4695. PMC: 8448967. DOI: 10.1158/0008-5472.CAN-21-1153. View

Crilly S, Puthenveedu M . Compartmentalized GPCR Signaling from Intracellular Membranes. J Membr Biol. 2020; 254(3):259-271. PMC: 8141539. DOI: 10.1007/s00232-020-00158-7. View

Nagata K, Tanaka K, Ogawa K, Kemmotsu K, Imai T, Yoshie O . Selective expression of a novel surface molecule by human Th2 cells in vivo. J Immunol. 1999; 162(3):1278-86. View

Pei S, Minhajuddin M, Callahan K, Balys M, Ashton J, Neering S . Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells. J Biol Chem. 2013; 288(47):33542-33558. PMC: 3837103. DOI: 10.1074/jbc.M113.511170. View

Jandl K, Heinemann A . The therapeutic potential of CRTH2/DP2 beyond allergy and asthma. Prostaglandins Other Lipid Mediat. 2017; 133:42-48. PMC: 7612073. DOI: 10.1016/j.prostaglandins.2017.08.006. View

10.

Dash P, Ghatak S, Topi G, Satapathy S, Ek F, Hellman K . High PGD receptor 2 levels are associated with poor prognosis in colorectal cancer patients and induce VEGF expression in colon cancer cells and migration in a zebrafish xenograft model. Br J Cancer. 2021; 126(4):586-597. PMC: 8854381. DOI: 10.1038/s41416-021-01595-4. View

11.

Matsuo Y, MacLEOD R, Uphoff C, Drexler H, Nishizaki C, Katayama Y . Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23). Leukemia. 1997; 11(9):1469-77. DOI: 10.1038/sj.leu.2400768. View

12.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

13.

Spierings D, McGoldrick D, Hamilton-Easton A, Neale G, Murchison E, Hannon G . Ordered progression of stage-specific miRNA profiles in the mouse B2 B-cell lineage. Blood. 2011; 117(20):5340-9. PMC: 3109709. DOI: 10.1182/blood-2010-10-316034. View

14.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

15.

Regad T . Targeting RTK Signaling Pathways in Cancer. Cancers (Basel). 2015; 7(3):1758-84. PMC: 4586793. DOI: 10.3390/cancers7030860. View

16.

Repasky G, Chenette E, Der C . Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?. Trends Cell Biol. 2004; 14(11):639-47. DOI: 10.1016/j.tcb.2004.09.014. View

17.

Cosmi L, Annunziato F, Galli MIG , Maggi RME , Nagata K, Romagnani S . CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur J Immunol. 2000; 30(10):2972-9. DOI: 10.1002/1521-4141(200010)30:10<2972::AID-IMMU2972>3.0.CO;2-#. View

18.

Zhang X, Settleman J, Kyriakis J, Elledge S, Marshall M, Bruder J . Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993; 364(6435):308-13. DOI: 10.1038/364308a0. View

19.

Shirasaki H, Kikuchi M, Kanaizumi E, Himi T . Accumulation of CRTH2-positive leukocytes in human allergic nasal mucosa. Ann Allergy Asthma Immunol. 2009; 102(2):110-5. DOI: 10.1016/S1081-1206(10)60239-6. View

20.

Takai T, Tsujino T, Yoshikawa Y, Inamoto T, Sugito N, Kuranaga Y . Synthetic miR-143 Exhibited an Anti-Cancer Effect via the Downregulation of K-RAS Networks of Renal Cell Cancer Cells In Vitro and In Vivo. Mol Ther. 2019; 27(5):1017-1027. PMC: 6520334. DOI: 10.1016/j.ymthe.2019.03.004. View