Small Non-coding RNA and Leukemia (NRL) group
Lines of research:
Functions of small non-coding RNA in normal hematopoiesis and disease: 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. This work is currently funded by a KWF grant (10948). In addition, I’m involved in a Horizon 2020 research and innovation program (reference: H2020-SC1-2016-2017, ImmunAID, personalised medicine, #779295, 2018-2023), in which we investigate miRNA in hematopoietic cells of patients with Auto-inflammatory disorders.
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. In close collaboration with Dr. Vincent van der Velden, we are currently investigating the oncogenic activities of aberrantly expressed snoRNAs in acute leukemia.
Creating a low-risk strategy for rapid and efficient engraftment after hematopoietic stem cell transplantation:
I started an ambitious research program on antibody-mediated depletion of HSCs with a postdoc and technician. This innovative approach will replace the conventional toxic BM conditioning treatments and will be extremely useful for all HSC transplantation treatments, including those of physically weak patients and patients with genetic diseases, which are normally excluded from treatment. Therefore, the successful antibodies will increase the clinical benefit of a large group of patients and strongly reduce medical costs. To achieve this goal, I successfully initiated collaborations with the company Harbour Biomed for improvement of HSC -depleting antibodies and with professors of the Hematology and Immunology departments of Erasmus MC (prof.drs. P. Katsikis, J. Cornelissen and M. van Hagen) and patient organization SAS (Stichting voor AfweerStoornissen). This Harbour Biomed – Erasmus MC consortium is funded by a Health-Holland grant of which I’m the project coordinator. I have the ambition to bring personalized HSCT personalized genome editing to correct genomic aberrations HSCs of or patients with chronic blood diseases to the clinic.
Our research is currently funded by KWF, Health-Holland and Horizon 2020.
For overview awards and research funding go to ORCID Erkeland: https://orcid.org/0000-0002-1019-7957
- 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.
- Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136-1152.
- Marks DI, Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood. 2017;129(9):1134-1142.
- Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281-297.
- 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.
- Alemdehy MF, Erkeland SJ. Stop the dicing in hematopoiesis: what have we learned? Cell Cycle. 2012;11(15):2799-2807.
- 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.
- 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.
- 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 (UD)
- Giada Dal Collo (post-doc)
- Martijn Verbeek (Msc.), PhD-student
- Christiaan Stavast (MSc.), PhD-student
- Srinaath Narasimhan (Master student)
- Antoinette van Hoven-Bijen (BSc., Senior Technician)
- Iris van Zuijen (MSc., researchTechnician)
- Yvette Caljouw, Research Assistant
- Tessa Alofs (Bsc. Technician)
- Tamara van Wees (Bsc. Technician)
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 of research.
(See for all publications Erkeland S in PubMed)
- MicroRNA-139 Expression Is Dispensable for the Generation of Influenza-Specific CD8+ T Cell Responses.
Hope JL, Zhao M, Stairiker CJ, Kiernan CH, Carey AJ, Mueller YM, van Meurs M, Brouwers-Haspels I, Otero DC, Bae EA, Faso HA, Maas A, de Looper H, Fortina PM, Rigoutsos I, Bradley LM, Erkeland SJ, Katsikis PD.
J Immunol. 2022 Jan 12: PMID: 3502227745. (IF: 5.422)
- miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia.
Assmann JLJC, Leon LG, Stavast CJ, van den Bogaerdt SE, Schilperoord-Vermeulen J, Sandberg Y, Bellido M, Erkeland SJ, Feith DJ, Loughran TP Jr, Langerak AW.
Leukemia. 2021 Dec 6. PMID: 34873301 (IF: 11.528)
- The tumor suppressor MIR139 is silenced by POLR2M to promote AML oncogenesis.
Stavast CJ, van Zuijen I, Karkoulia E, Özçelik A, van Hoven-Beijen A, Leon LG, Voerman JSA, Janssen GMC, van Veelen PA, Burocziova M, Brouwer RWW, van IJcken WFJ, Maas A, Bindels EM, van der Velden VHJ, Schliehe C, Katsikis PD, Alberich-Jorda M, Erkeland SJ. (corresponding author)
Leukemia. 2021 Nov 5. PMID: 34741119 (IF: 11.528)
- Extracellular Vesicles Derived From Adult and Fetal Bone Marrow Mesenchymal Stromal Cells Differentially Promote ex vivo Expansion of Hematopoietic Stem and Progenitor Cells.
Ghebes CA, Morhayim J, Kleijer M, Koroglu M, Erkeland SJ, Hoogenboezem R, Bindels E, van Alphen FPJ, van den Biggelaar M, Nolte MA, van der Eerden BCJ, Braakman E, Voermans C, van de Peppel J.
Front Bioeng Biotechnol. 2021 Feb 25;9:640419. doi: 10.3389/fbioe.2021.640419. eCollection 2021.
PMID: 33718342 (IF: 5.48)
- The miR-200c/141-ZEB2-TGFβ axis is aberrant in human T-cell prolymphocytic leukemia.
Erkeland SJ, Stavast CJ, Schilperoord-Vermeulen J, Dal Collo G, Van de Werken HJG, Leon LG, Van Hoven-Beijen A, Van Zuijen I, Mueller YM, Bindels EM, De Ridder D, Kappers-Klunne MC, Van Lom K, Van der Velden VHJ, Langerak AW. (corresponding author)
Haematologica. 2021 Feb 18. PMID: 33596640 (IF: 9.941)
- Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation.
Zhao M, Kiernan CH, Stairiker CJ, Hope JL, Leon LG, van Meurs M, Brouwers-Haspels I, Boers R, Boers J, Gribnau J, van IJcken WFJ, Bindels EM, Hoogenboezem RM, Erkeland SJ, Mueller YM, Katsikis PD.
PLoS Pathog. 2020 Jun 24 (IF: 6.823)
- Identification of osteolineage cell-derived extracellular vesicle cargo implicated in hematopoietic support.
Morhayim J, Ghebes CA, Erkeland SJ, Ter Borg MND, Hoogenboezem RM, Bindels EMJ, van Alphen FPJ, Kassem M, van Wijnen AJ, Cornelissen JJ, van Leeuwen JP, van der Eerden BCJ, Voermans C, van de Peppel J, Braakman E.
FASEB J. 2020 Apr;34(4):5435-5452. (IF: 5.191)
- The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation.
Stavast CJ, Erkeland SJ. Invited review (corresponding author)
Cells. 2019 Nov 19;8(11):1465. (IF: 6.600)
- A functional variant in the miR-142 promoter modulating its expression and conferring risk of Alzheimer disease.
Ghanbari M, Munshi ST, Ma B, Lendemeijer B, Bansal S, Adams HH, Wang W, Goth K, Slump DE, van den Hout MCGN, van IJcken WFJ, Bellusci S, Pan Q, Erkeland SJ, de Vrij FMS, Kushner SA, Ikram MA.
Hum Mutat. 2019 Nov;40(11):2131-2145. (IF: 4.603)
- The interplay between critical transcription factors and microRNAs in the control of normal and malignant myelopoiesis
Stavast CJ, Leenen PJM, Erkeland SJ (corresponding author)
Cancer Lett. 2018 Jul 28;427:28-37. (IF: 8.679)