Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies

The Journal of Clinical Investigation
Utthara NayarEthel Cesarman

Abstract

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in trea...Continue Reading

References

Jul 1, 1978·Proceedings of the National Academy of Sciences of the United States of America·R C WillisJ E Seegmiller
Jan 1, 1990·Pharmacology & Therapeutics·W B Parker, Y C Cheng
Feb 15, 1985·The Biochemical Journal·A C Newby
Jan 1, 1965·Advances in Chemotherapy·G B Elion, G H Hitchings
Sep 1, 1983·The Journal of Antimicrobial Chemotherapy·G B Elion
May 4, 1995·The New England Journal of Medicine·E CesarmanD M Knowles
Jan 1, 1993·Cardiovascular Research·R M Berne
Oct 27, 1998·AIDS Research and Human Retroviruses·R G PtakJ C Drach
Aug 10, 1999·Journal of Virology·I JordanW I Lipkin
May 9, 2002·Proceedings of the National Academy of Sciences of the United States of America·Detlev BoisonHanns Mohler
Aug 2, 2003·Journal of Cell Science·Nigel FieldMary Collins
Aug 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richard G JennerPaul Kellam
Mar 1, 1961·Journal of Medicinal and Pharmaceutical Chemistry·J A MONTGOMERYF M SCHABEL
Apr 7, 2004·The Journal of Experimental Medicine·Ilaria GuasparriEthel Cesarman
Mar 17, 2007·The Journal of Clinical Investigation·Grzegorz SarekPäivi M Ojala
Jul 5, 2008·Nucleosides, Nucleotides & Nucleic Acids·S GiglioniD Vannoni
Oct 29, 2008·Oncogene·B EwaldW Plunkett
Dec 3, 2008·Handbook of Experimental Pharmacology·E De Clercq, J Neyts
Jul 29, 2009·Biochemical and Biophysical Research Communications·Xianying Amy CuiRadhey S Gupta
Jan 8, 2010·Molecular Cancer Therapeutics·Jennifer Ann Frey, Varsha Gandhi
Oct 5, 2010·Current Opinion in Cell Biology·Kimberly McCall
Dec 2, 2011·Clinical and Investigative Medicine. Médecine Clinique Et Experimentale·Katherine Lb Borden
Feb 14, 2012·Nature Chemical Biology·Sarah A WackerTarun M Kapoor
Jun 16, 2012·Glia·Detlev Boison
Mar 28, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kyoko MoriNobuyuki Kato
Apr 10, 2013·Scientific Reports·Javier Rivera GuzmanChristian Jobin
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Jun 1, 2013·Nature Reviews. Drug Discovery·Lars Petter JordheimCharles Dumontet
Jun 16, 2014·Nature Chemical Biology·Corynn KasapTarun M Kapoor

❮ Previous
Next ❯

Citations

Apr 9, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Donal McHughChristian Münz
Feb 2, 2019·Nature Reviews. Disease Primers·Ethel CesarmanDenise Whitby
May 29, 2019·Nucleosides, Nucleotides & Nucleic Acids·Agha Zeeshan Mirza
Jul 31, 2021·International Journal of Nanomedicine·Ran ChenJingqing Zhang

❮ Previous
Next ❯

Datasets Mentioned

BETA
PRJNA362820

Methods Mentioned

BETA
flow cytometry
reverse transcription PCR
xenograft
biopsy
RNA-Seq
xenografts

Software Mentioned

Protein Preparation Wizard ( Schrödinger )
Maestro
Schrödinger
FlowJo
Ingenuity Pathway Analysis ( QIAGEN )
GraphPad prism

Related Concepts

Related Feeds

B cell Differentiation

Depending on the signal received through the B cell receptor and other receptors, B cells differentiate into follicular or marginal zone B cells. Here is the latest research pertaining to this differentiation process.

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.

Castleman Disease

Castleman disease is a rare disorder that involves an overgrowth of cells in the lymph nodes. Unicentric Castleman disease affects one lymph node, usually in the chest or abdomen. Multicentric Castleman disease affects multiple lymph nodes, commonly located in the neck, collarbone, underarm and groin areas. Discover the latest research on Castleman disease here.