GLI2 inhibition abrogates human leukemia stem cell dormancy

Autor: Anil Sadarangani, Daniel Goff, Annelie E. Abrahamsson Schairer, Catriona Jamieson, Todd VanArsdale, Richard A. Moore, Karen Messer, Lei Bao, Marco A. Marra, Thomas J. Hudson, Ifat Geron, Michael John Munchhof, Minya Pu, Kathleen M. Lennon, Russell Wall, Mark D. Minden, Sheldon R. Morris, Gabriel Pineda, Angela C. Court, Tannishtha Reya, Amy Jackson-Fisher, John Douglas Mcpherson, Hanna K. A. Mikkola, Sacha L. Prashad, Alice Shih, Hye Jung E. Chun
Rok vydání: 2015
Předmět:
Smoothened SMO
GLI2
Medical and Health Sciences
Mice
0302 clinical medicine
Stem Cell Research - Nonembryonic - Human
Cancer
Medicine(all)
Pediatric
Mice
Knockout
0303 health sciences
Leukemia
Reverse Transcriptase Polymerase Chain Reaction
Sonic hedgehog
Nuclear Proteins
Myeloid leukemia
Hematology
General Medicine
Cell cycle
Fetal Blood
PF-04449913
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Stem Cell Research - Nonembryonic - Non-Human
Stem cell
Tyrosine kinase
Leukemia stem cells
Biotechnology
Stromal cell
Knockout
Immunology
Kruppel-Like Transcription Factors
Zinc Finger Protein Gli2
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Rare Diseases
Clinical Research
Genetics
medicine
Animals
Humans
Hedgehog Proteins
Progenitor cell
DNA Primers
030304 developmental biology
Base Sequence
Biochemistry
Genetics and Molecular Biology(all)
Research
Human Genome
Stem Cell Research
medicine.disease
Coculture Techniques
Cancer research
Transcriptome
Smoothened
Zdroj: Journal of Translational Medicine
Journal of translational medicine, vol 13, iss 1
Sadarangani, A; Pineda, G; Lennon, KM; Chun, HJ; Shih, A; Schairer, AE; et al.(2015). GLI2 inhibition abrogates human leukemia stem cell dormancy. Journal of Translational Medicine, 13(1), 1. doi: 10.1186/s12967-015-0453-9. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/1176d581
ISSN: 1479-5876
Popis: Background Dormant leukemia stem cells (LSC) promote therapeutic resistance and leukemic progression as a result of unbridled activation of stem cell gene expression programs. Thus, we hypothesized that 1) deregulation of the hedgehog (Hh) stem cell self-renewal and cell cycle regulatory pathway would promote dormant human LSC generation and 2) that PF-04449913, a clinical antagonist of the GLI2 transcriptional activator, smoothened (SMO), would enhance dormant human LSC eradication. Methods To test these postulates, whole transcriptome RNA sequencing (RNA-seq), microarray, qRT-PCR, stromal co-culture, confocal fluorescence microscopic, nanoproteomic, serial transplantation and cell cycle analyses were performed on FACS purified normal, chronic phase (CP) chronic myeloid leukemia (CML), blast crisis (BC) phase CML progenitors with or without PF-04449913 treatment. Results Notably, RNA-seq analyses revealed that Hh pathway and cell cycle regulatory gene overexpression correlated with leukemic progression. While lentivirally enforced GLI2 expression enhanced leukemic progenitor dormancy in stromal co-cultures, this was not observed with a mutant GLI2 lacking a transactivation domain, suggesting that GLI2 expression prevented cell cycle transit. Selective SMO inhibition with PF-04449913 in humanized stromal co-cultures and LSC xenografts reduced downstream GLI2 protein and cell cycle regulatory gene expression. Moreover, SMO inhibition enhanced cell cycle transit and sensitized BC LSC to tyrosine kinase inhibition in vivo at doses that spare normal HSC. Conclusion In summary, while GLI2, forms part of a core HH pathway transcriptional regulatory network that promotes human myeloid leukemic progression and dormant LSC generation, selective inhibition with PF-04449913 reduces the dormant LSC burden thereby providing a strong rationale for clinical trials predicated on SMO inhibition in combination with TKIs or chemotherapeutic agents with the ultimate aim of obviating leukemic therapeutic resistance, persistence and progression. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0453-9) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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