Stefan J. Erkeland, PhD

Assistant Professor
Department of Immunology
Small Non-coding RNA and Leukemia (NRL) group

s.erkeland@erasmusmc.nl

Small Non-coding RNA and Leukemia (NRL) group

Our research group investigates the functions of small non-coding RNAs, including microRNAs (miRNAs) and small nucleolar RNAs (snoRNAs), in normal and malignant hematopoiesis. MiRNAs are short, non-coding RNA ranging in length from 19 to 23 nucleotides and exert a regulatory effect on cellular transcripts by binding to them in a sequence dependent manner and affecting mRNA stability and translation 4. One typical attribute of miRNA expression is their tissue- and cell-state-dependent nature. The importance of miRNAs in hematopoiesis was implied by demonstrating that deletion of DICER in hematopoietic stem cells, an endonuclease critical for the maturation of miRNAs, leads to loss of hematopoiesis 5. Also, deletion of DICER in hematopoietic progenitors impairs differentiation and cellular functions 6. MiRNAs are deregulated in acute leukemia. We found that some miRNAs, such miR-199 and miR-155 are strong oncogenes and drive leukemic transformation of hematopoietic stem and progenitor cells. Furthermore, we found that other miRNAs, such as miR-139, are strong tumor suppressors and are frequently downregulated in acute leukemia 7,8. With my research group I try to understand the functions of these miRNAs in the complex process of oncogenic transformation of hematopoietic stem and progenitor cells towards leukemia.

From left to right: Dr. Stefan Erkeland (PI), Iris van Zuijen (Technician), Antoinette van Hoven-Beijen (Senior Technician), Christiaan Stavast (PhD-student), Manon Gloudemans (HLO-student), Tamara Buurman (HLO-student)

SnoRNAs: SnoRNAs belong to the class of non-coding RNAs, and are critical for normal development of a broad range of organisms, including plants, insects, worms and mammals. SnoRNAs are highly conserved between species and control post-transcriptional RNA processing. In general, their length varies from 60 to 170 nucleotides. SnoRNAs can be divided into three major subfamilies based on structure and function: C/D box snoRNAs (snoRDs), H/ACA box snoRNAs (snoRAs) and Cajal body-specific snoRNAs (scaRNAs) 9. Ribosomes are the protein factories in all cells and consist of a complex of ribosomal RNAs (rRNA) and proteins. Recently published data show that snoRNAs control gene expression in many different ways, amongst other by the regulation of the ribosome. Deregulated snoRNA expression affects mRNA stability, ribosome structure and function and protein expression. Consequently, this results in overexpression of oncogenes and/or loss of tumor-suppressor proteins, which are hallmarks of cancer. There is initial evidence that enhanced expression of individual snoRNAs promote different types of human cancer including lung cancer and breast cancer. We are currently investigating the oncogenic activities of aberrantly expressed snoRNAs in leukemia.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
  2. Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136-1152.
  3. Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017;129(9):1134-1142.
  4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-297.
  5. Guo S, Lu J, Schlanger R, et al. MicroRNA miR-125a controls hematopoietic stem cell number. Proc Natl Acad Sci U S A. 2010;107(32):14229-14234.
  6. Alemdehy MF, Erkeland SJ. Stop the dicing in hematopoiesis: what have we learned? Cell Cycle. 2012;11(15):2799-2807.
  7. Alemdehy MF, de Looper HW, Kavelaars FG, et al. MicroRNA-155 induces AML in combination with the loss of C/EBPA in mice. Leukemia. 2016;30(11):2238-2241.
  8. Alemdehy MF, Haanstra JR, de Looper HW, et al. ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation. Blood. 2015;125(25):3937-3948.
  9. Bachellerie JP, Cavaille J, Huttenhofer A. The expanding snoRNA world. Biochimie. 2002;84(8):775-790.

Left: Manon Gloudemans Right: Christiaan Stavast. A) Cumulative survival of mice transplanted with hematopoietic stem and progenitor cells expressing EGFP with, miR-199a (n=5), (p<0.0005 compared to EV (EGFP only) n=9), miR-106 (n=4) (a non-oncogenic miRNA that promotes myeloid progenitor expansion),  or secondary recipients of miR-199a leukemia cells (n=7)(p<0,0005 compared to EV). B) Micrographs showing the morphology of leukemia blasts in the spleen.

Current Group Members

  • Stefan Erkeland, Research group leader, assistant professor
  • Antoinette van Hoven-Beijen (BSc., Senior Technician)
  • Christiaan Stavast (MSc.), PhD student
  • Iris van Zuijen (MSc., Technician)
  • Yvette Caljouw, Research Assistant
  • Noud Verstappen (HLO-student, Avans University of Applied Sciences)
  • Stijn van den Broek (HLO-student, University of Applied Sciences, Utrecht)

We are always looking for new talent. Please contact us when you are searching for an internship (MSc. or BSc.) or job position in an exciting field

Selected publications

(See for all publications Erkeland S in PubMed)

1. A functional variant in the miR-142 promoter modulating its expression and conferring risk of Alzheimer disease.
Mohsen Ghanbari, Shashini T. Munshi, Buyun Ma, Bas Lendemeijer, Sakshi Bansal, Hieab H. Adams, Wenshi Wang, Kerstin Goth, Denise E. Slump, Mirjam C.G.N van den Hout, Wilfred F.J. van IJcken, Saverio Bellusci, Qiuwei Pan, Stefan J. Erkeland, Femke M.S. de Vrij, Steven A. Kushner, M. Arfan Ikram
Human Mutation. 2019 Juli 19. doi: 10.1002/humu.23872

2. The interplay between critical transcription factors and microRNAs in the control of normal and malignant myelopoiesis.
Stavast CJ, Leenen PJM, Erkeland SJ.
Cancer Lett. 2018 Jul 28;427:28-37.

3. The Transcription Factor T-Bet Is Regulated by MicroRNA-155 in Murine Anti-Viral CD8+ T Cells via SHIP-1.
Hope JL, Stairiker CJ, Spantidea PI, Gracias DT, Carey AJ, Fike AJ, van Meurs M, Brouwers-Haspels I, Rijsbergen LC, Fraietta JA, Mueller YM, Klop RC, Stelekati E, Wherry EJ, Erkeland SJ, Katsikis PD.
Front Immunol. 2017 Dec 6;8:1696.

4. MicroRNA-155 induces AML in combination with the loss of C/EBPA in mice.
Alemdehy MF, de Looper HW, Kavelaars FG, Sanders MA, Hoogenboezem R, Löwenberg B, Valk PJ, Touw IP, Erkeland SJ.
Leukemia. 2016 Nov;30(11):2238-2241.

5. Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors.
Wojtowicz EE, Lechman ER, Hermans KG, Schoof EM, Wienholds E, Isserlin R, van Veelen PA, Broekhuis MJ, Janssen GM, Trotman-Grant A, Dobson SM, Krivdova G, Elzinga J, Kennedy J, Gan OI, Sinha A, Ignatchenko V, Kislinger T, Dethmers-Ausema B, Weersing E, Alemdehy MF, de Looper HW, Bader GD, Ritsema M, Erkeland SJ, Bystrykh LV, Dick JE, de Haan G.
Cell Stem Cell. 2016 Sep 1;19(3):383-96.

6. ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation.
Alemdehy MF, Haanstra JR, de Looper HW, van Strien PM, Verhagen-Oldenampsen J, Caljouw Y, Sanders MA, Hoogenboezem R, de Ru AH, Janssen GM, Smetsers SE, Bierings MB, van Veelen PA, von Lindern M, Touw IP, Erkeland SJ.
Blood. 2015 Jun 18;125(25):3937-48.

7. Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice.
Alemdehy MF, van Boxtel NG, de Looper HW, van den Berge IJ, Sanders MA, Cupedo T, Touw IP, Erkeland SJ.
Blood. 2012; 119:4723-30.

8. MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice.
Meenhuis A, van Veelen PA, de Looper H, van Boxtel N, van den Berge IJ, Sun SM, Taskesen E, Stern P, de Ru AH, van Adrichem AJ, Demmers J, Jongen-Lavrencic M, Lowenberg B, Touw IP, Sharp PA, Erkeland SJ.
Blood. 2011; 118:916-25.

9. Targeted deletion reveals essential and overlapping functions of the miR-17~92 family of miRNA clusters.
Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, Newman J, Bronson RT, Crowley D, Stone JR, Jaenisch R, Sharp PA, Jacks T.
Cell. 2008; 132:875-86.

10. Suppression of non-small cell lung tumor development by the let-7 microRNA family. Kumar MS, Erkeland SJ (shared first authorship), Pester RE, Chen CY, Ebert MS, Sharp PA, Jacks T.
Proc Natl Acad Sci U S A. 2008; 105:3903-8.

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