Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

SUMOylation of sPRDM16 promotes the progression of acute myeloid leukemia

Authors: Song Dong, Jieping Chen

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

In addition to genetic and epigenetic alteration, post-translational modification of proteins plays a critical role in the initiation, progression and maturation of acute myeloid leukemia (AML).

Methods

The SUMOylation site of sPRDM16 at K568 was mutated to arginine by site-directed mutagenesis. THP-1 acute myeloid leukemia cells were transduced with a lentivirus containing wild type or K568 mutant sPRDM16. Proliferation, self-renewal and differentiation of transduced THP-1 cells were analyzed both in vitro cell culture and in mouse xenografts. Gene expression profiles were analyzed by RNA-seq.

Results

Overexpression of sPRDM16 promoted proliferation, enhanced self-renewal capacity, but inhibited differentiation of THP-1 acute myeloid leukemia cells. We further confirmed that K568 is a bona fide SUMOylation site on sPRDM16. Mutation of the sPRDM16 SUMOylation site at K568 partially abolished the capacity of sPRDM16 to promote proliferation and inhibit differentiation of acute myeloid leukemia cells both in vitro and in mouse xenografts. Furthermore, THP-1 cells overexpressing sPRDM16-K568R mutant exhibited a distinct gene expression profile from wild type sPRDM16 following incubation with PMA.

Conclusions

Our results suggest that K568 SUMOylation of sPRDM16 plays an important role in the progression of acute myeloid leukemia.
Literature
1.
Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, DiRuscio A, et al. Sox4 is a key oncogenic target in C/EBPalpha mutant acute myeloid leukemia. Cancer Cell. 2013;24(5):575–88.CrossRefPubMedPubMedCentral
2.
de la Cruz-Herrera CF, Campagna M, Lang V, del Carmen González-Santamaría1 J, Marcos-Villar1 J, Rodríguez MS, et al. SUMOylation regulates AKT1 activity. Oncogene. 2015;34(11):1442–50.CrossRefPubMed
3.
Shimahara A, Yamakawa N, Nishikata I, Morishita K. Acetylation of lysine 564 adjacent to the C-terminal binding protein-binding motif in EVI1 is crucial for transcriptional activation of GATA2. J Biol Chem. 2010;285(22):16967–77.CrossRefPubMedPubMedCentral
4.
Tatham MH, Geoffroy M-C, Shen L, Plechanovova A, Hattersley N, Jaffray EG, et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008;10(5):538–46.CrossRefPubMed
5.
Ivanschitz1 L, DeThé H, Le Bras M. PML, SUMOylation, and Senescence. Front Oncol. 2013;3:171–8.
6.
Bossis G, Sarry J-E, Kifagi C, Ristic M, Saland E, Vergez F, et al. The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. Cell Rep. 2014;7(6):1815–23.CrossRefPubMed
7.
Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, et al. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1–EVI1 gene and is transcriptionally activated in t(1 3)(p36 q21)-positive leukemia cells. Blood. 2000;96(9):3209–14.PubMed
8.
Di Zazzo E, De Rosa C, Abbondanza C, Moncharmont B. PRDM Proteins: Molecular Mechanisms in Signal Transduction and Transcriptional Regulation. Biology. 2013;2(1):107–41.CrossRefPubMedPubMedCentral
9.
Nishikata I, Sasaki H, Iga M, Tateno Y, Imayoshi S, Asou N, et al. A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Blood. 2003;102(9):3323–32.CrossRefPubMed
10.
Shing DC, Trubia M, Marchesi F, Radaelli E, Belloni E, Tapinassi C, et al. Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice. J Clin Invest. 2007;117(12):3696–707.PubMedPubMedCentral
11.
Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010;19(5):774–89.CrossRefPubMed
12.
Aguilo F, Avagyan S, Labar A, Sevilla A, Lee D-F, Kumar P, et al. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011;117(19):5057–66.CrossRefPubMedPubMedCentral
13.
Chuikov1 S, Levi1 BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010;12(10):999–1006.
14.
Seale1 P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961–7.
15.
Kajimura S, Seale1 P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009;460(7259):1154–8.
16.
Villanueva CJ, Vergnes L, Wang J, Drew BG, Hong C, Tu Y, et al. Adipose subtype-selective recruitment of TLE3 or Prdm16 by PPARgamma specifies lipid storage versus thermogenic gene programs. Cell Metab. 2013;17(3):423–35.CrossRefPubMedPubMedCentral
17.
Ohno1 H, Shinoda1 K, Ohyama1 K, Sharp LZ, Kajimura S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature. 2013;504(7478):163–7.
18.
Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, et al. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012;156(1):76–88.CrossRefPubMed
19.
Geiss-Friedlander R, MelchiorF. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 2007;8(12):947–56.
20.
21.
Sarge1 KD, Park-Sarge O-K. Sumoylation and human disease pathogenesis. Trends Biochem Sci. 2009;34(4):200–5.
22.
Nishikata I, Nakahata S, Saito Y, Kaneda K, Ichihara E, Yamakawa N, et al. Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation. Oncogene. 2011;30(40):4194–207.CrossRefPubMed
23.
24.
Li MJ, Rossi JJ. Lentivirus Transduction of Hematopoietic Cells. Cold Spring Harb Protoc. 2007;2007(5):pdb.prot4755.
25.
Duan C-W, Shi J, Chen J, Wang B, Yu Y-H, Qin X, et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell. 2014;25(6):778–93.CrossRefPubMed
26.
Harms MJ, Ishibashi J, Wang W, Lim H-W, Goyama S, Sato T, et al. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab. 2014;19(4):593–604.CrossRefPubMedPubMedCentral
27.
28.
Yoshida M, Nosaka K, Yasunaga J, Nishikata I, Morishita K, Matsuoka M. Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells. Blood. 2004;103(7):2753–60.CrossRefPubMed
29.
Pinheiro I, Margueron R, Shukeir N, Eisold M, Fritzsch C, Richter FM, et al. Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell. 2012;150(5):948–60.CrossRefPubMed
30.
van Waalwijk van Doorn-Khosrovani SB, Erpelinck C, van Putten WLJ, Valk PJM, van der Poel-van de Luytgaarde S, Hack R, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood. 2003;101(3):837–45.CrossRef
31.
Neyret-Kahn H, Benhamed M, Ye T, Le Gras S, Cossec J-C, Lapaquette P, et al. Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation. Genome Res. 2013;23(10):1563–79.CrossRefPubMedPubMedCentral
32.
Singh S, Pradhan AK, Chakraborty S. SUMO1 negatively regulates the transcriptional activity of EVI1 and significantly increases its co-localization with EVI1 after treatment with arsenic trioxide. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2013;1833(10):2357–68.CrossRef
33.
Zhang W, Wang X, Xia X, Liu X, Suo1 S, Guo J, et al. Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages. Eur J Immunol. 2013;43(1):258–69.CrossRefPubMed
34.
Kreise D, Sugimoto S, Tietjens J, Zhu J, Yamamoto S, Krupnick AS, et al. Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis. J Clin Invest. 2011;121(1):265–76.CrossRef
35.
Yuan Z, Peng L, Radhakrishnan R, Seto E. Histone Deacetylase 9 (HDAC9) Regulates the Functions of the ATDC (TRIM29) Protein. Journal of Biological Chemistry. 2010;285(50):39329–38.CrossRefPubMedPubMedCentral
36.
Hussen J, Frank C, Düvel A, Koy M, Schuberth H-J. The chemokine CCL5 induces selective migration of bovine classical monocytes and drives their differentiation into LPS-hyporesponsive macrophages in vitro. Developmental & Comparative Immunology. 2014;47(2):169–77.CrossRef
37.
Gulino A, Di Marcotullio L, Screpanti I. The multiple functions of Numb. Exp Cell Res. 2010;316(6):900–6.CrossRefPubMed
38.
Subramaniam M, Hawse JR, Rajamannan NM, Ingle JN, Spelsberg TC. Functional role of KLF10 in multiple disease processes. Biofactors. 2010;36(1):8–18.PubMedPubMedCentral
39.
Pece S, Confalonieri S, Romano PR, Di Fiore PP. NUMB-ing down cancer by more than just a NOTCH. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2011;1815(1):26–43.CrossRef
Metadata
Title
SUMOylation of sPRDM16 promotes the progression of acute myeloid leukemia
Authors
Song Dong
Jieping Chen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1844-2

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation

Research article

Sorafenib suppresses the epithelial-mesenchymal transition of hepatocellular carcinoma cells after insufficient radiofrequency ablation

Research article

Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta-analysis of published studies involving 32 studies

Research article

NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas

Research article

Prevalence and outcomes of extrahepatic primary malignancy associated with Hepatocellular Carcinoma in a Korean population

Research article

The Aplidin analogs PM01215 and PM02781 inhibit angiogenesis in vitro and in vivo
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits