Rebekka K.M. Schneider, MD, PhD

CELLULAR KEY DRIVERS OF BONE MARROW FIBROSIS

Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure. We demonstrated that Gli1+ cells are fibrosis-driving cells in BM fibrosis, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. We further demonstrate that mesenchymal stromal progenitor cells are fibrosis-driving cells in mice and patients, that inflammation in the bone- marrow stroma precedes TGF-b signaling-driven fibrosis, and that the alarmin heterocomplex S100A8/S100A9 holds promise as MPN progression marker and therapeutic target Based on this work, we are preparing a clinical proof-of-concept trial translating our findings from pre-clinical models to improved treatments for patients.

In ongoing projects, we are diving deeper into mechanisms how fibrosis-driving cells are activated, how this is determined by the micro- and macro- bone marrow niche and on validating novel therapeutic targets and improved diagnostic markers.

Hematological Malignancies and Chronic Inflammatory Diseases

Chronic inflammatory diseases can have a significant effect on normal blood formation. A kidney-bone marrow cross-talk is indisputable as the kidneys filter the blood around 40x/day. However, this cross-talk is far less understood when the functions of either the bone marrow (e.g. through blood cancer) or the kidneys (e.g. chronic kidney disease; CKD) are impaired. In ongoing work, we focus on the  vicious and mutual cross-talk between altered hematopoiesis and CKD.

BONE MARROW and KIDNEY IN A DISH

We have a long-standing interest in recapitulating organs in a dish using human cells or even patient-derived cells for pre-clinical testing. We have collaborations to apply different (smart) materials to provide specific structures for cells to grow, have patient-derived induced pluripotent stem cells (iPS cells) and generated organoids, in particular kidney organoids. We used these kidney organoids to identify the effect of SARS-COV2 on the kidney which correlated well with the situation in patients and helped to uncover a pro-fibrotic effect of SARS-Cov2 on organs.

Contact info:
r.k.schneider@erasmusmc.nl
Dept. of Developmental Biology
Erasmus MC

Rebekka is a physician-scientist and received her M.D. degree from RWTH Aachen University, Germany, in 2007 and her Ph.D. degree from Erasmus MC University, the Netherlands, in 2017. Rebekka is the director of the Department for Cell and Tumor Biology at RWTH Aachen, Germany, a Principal Investigator (Associate Professor) at Erasmus MC, Netherlands and a Principal Investigator at the Oncode Institute. She was a postdoctoral fellow in Benjamin Ebert’s lab (Brigham and Women’s Hospital, Harvard Medical School, Boston) and focused on the role of genetic haploinsufficiency in hematopoietic stem cell biology and targeted therapy of del(5q) myelodysplastic syndrome. 

Her primary focus is disease-oriented laboratory investigation of clonal myeloid neoplasms, employing a range of genomic technologies as well as classical cellular and molecular biology experimental approaches. She has a long-standing interest in dissecting the interaction between hematopoietic cells and the bone marrow niche, in both steady state and myeloid neoplasms. During her fellowship in Pathology with focus on Hematopathology she started to wonder which cells in the bone marrow are responsible for the deposition of fibers in bone marrow fibrosis in myeloproliferative neoplasms. She was particularly frustrated that fibrosis can only be diagnosed when it is already present with standard methods but that it is difficult to predict if a patient will develop fibrosis and that there are no specific anti-fibrotic treatments. This was the starting point for a majority of projects in the lab focusing on understanding fibrosis-driving cells and their activating mechanisms in blood cancer. Additionally, she is very interested in understanding how the hematopoietic stem cell transforms into a malignant cell in blood cancer and how external stimuli (like inflammation and chronic diseases) affect this process. 

Selected Publications

1. Leimkühler NB, Gleitz HFE, Ronghui L, Snoeren IAM , Fuchs SNR, Nagai JS, Banjanin B, Lam KH, Vogl T, Kuppe C, Stalmann USA, Buesche G, Kreipe H, Gütgemann I, Krebs P, Banz Y, Boor P, Wing-Ying E, Brümmendorf TH, Koschmieder S, Crysandt M, Bindels E, Kramann R, Costa IG and Schneider RK. Heterogeneous bone marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis; Cell Stem Cell 2021 Apr 1;28(4):637-652.e8. doi: 10.1016/j.stem.2020.11.004

2. Jansen J, Reimer KC, Nagai JS, Varghese FS, Overheul GJ, de Beer M, Roverts R, Daviran D, Fermin LAS, Willemsen B, Beukenboom M, Djudjaj S, von Stillfried und Rattonitz S, van Eijk LE, Mastik M, Bulthuis M, den Dunnen W, van Goor H , Hillebrands JL, Triana SH, Alexandrov T, Timm MC, Tideman van den Berge T, van den Broek M, Nlandu Q, Heijnert J, Mooren F, Kuppe C, Miesen P, Grünberg K, Ijzermans J, Steenbergen T, Czogalla J…and Costa IG#, Schneider RK#, Smeets B# and Kramann R#. SARS-CoV-2 infects kidney cells and causes kidney fibrosis. Cell Stem Cell 2022 Feb 3;29(2):217-231. #equal contribution.

3. Stalmann USA, Banjanin B, Snoeren IAM, Nagai JS, Leimkühler NB, Li R, Benabid A, Pritchard JE, Malyaran H, Neuss S, Bindels EM, Costa IG, Schneider RK. Single-cell analysis of cultured bone marrow stromal cells reveals high similarity to fibroblasts in situ. Exp Hematol 2022 Mar; epub ahead of print

4. Stalmann USA, Ticconi F, Snoeren IAM, Li R, Gleitz HFE, Cowley GS, McConkey ME, Wong AB, Schmitz S, Fuchs SNR, Sood S, Leimkühler NB, Martinez-Høyer S, Banjanin B, Root D, Brümmendorf TH, Pearce JE, Schuppert A, Bindels EMJ, Essers MA, Heckl D, Stiehl T, Costa IG, Ebert BL, Schneider RK. Genetic barcoding systematically compares genes in del(5q) MDS and reveals a central role for CSNK1A1 in clonal expansion. Blood Adv. 2022 Mar 22;6(6):1780-1796.

5. Gleitz H, Dugourd AJF, Leimkühler NB, Snoeren IAM, Fuchs SNR, Menzel S, Ziegler S, Kroeger N, Triviai I, Büsche G, Kreipe H, Banjanin B, Pritchard J, Hoogenboezem R, Bindels E, Schumacher N, Rose-John S, Elf S, Saez-Rodriguez J, Kramann R, Schneider RK. Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN. Blood. 2020 Jul 29:blood.2019004095. doi: 10.1182/blood.2019004095. 

6. Ribezzo F*, Snoeren IAM*, Ziegler S, Stoelben J, Olofsen PA, Henic A, Ventura Ferreira M, Chen S, Stalmann USA, Buesche G, Hoogenboezem RM, Kramann R, Platzbecker U, Raaijmakers MHGP, Ebert BL and Schneider RK. Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome. Leukemia, volume 33, pages1759–1772(2019)

7. Kramann R, Schneider RK. The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis. Blood. 2018 May 10;131(19):2111-2119. 

8. Schneider R. K.#, Mullally A., Dugourd A., Peisker F., Hoogenboezem R., van Strien P. M., Bindels E. M., Heckl D., Büsche G., Fleck D., Müller-Newen G., Wongboonsin J., Ventura Ferreira M., Puelles V. G., Saez-Rodriguez J., Ebert B. L., Humphreys B. D., Kramann R.#. (2017): Gli1+ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target. Cell Stem Cell, 2018 Aug 2;23(2):308-309.  #corresponding author

9. Kramann R, Goettsch C, Wongboonsin J, Iwata H, Schneider RK, Kuppe C, Kaesler N, Chang-Panesso M, Machado FG, Gratwohl S, Madhurima K, Hutcheson JD, Jain S, Aikawa E, Humphreys BD. Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease. Cell Stem Cell. 2016 Nov 3;19(5):628-642.

10. Obeng EA, Chappell RJ, Seiler M, Chen MC, Campagna D, Schmidt PJ, Schneider RK,  Yu L, Lord AM, McConkey ME, Ali AM, Raza A, Buonamici S, Smith PG, Mullally A, Wu CJ, Fleming MD and Ebert BL. Physiologic expression of Sfb1K700E causes impaired erythropoiesis, aberrant splicing, and sensitivity to a spliceosome inhibitor. Cancer Cell. 2016 Sep 12;30(3):404-17.

11. Schneider RK, Schenone M, Ventura Ferreira M, Kramann R, Joyce CE, Hartigan C Beier F, Brümmendorf TH, Germing U, Platzbecker U, Büsche G, Knüchel R, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8/S100A9. Nature Medicine 2016 Mar;22(3):288-97. 

12. Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, Tothova Z, Tejero H, Heckl D, Järås M, Chen M, Li H, Tamayo A, Cowley GS, Rozenblatt-Rosen O, Al-Shahrour F, Regev A, Ebert BL. Core circadian clock genes regulate leukemia stem cells in AML. Cell. 2016 Apr 7;165(2):303-16. 

13. Wen JQ, Yang Q, Goldenson B, Malinge S, Lasho T, Schneider RK, Breyfogle LJ, Schultz R, Gilles L, Koppikar P, Abdel-Wahab O, Pardanani A, Stein B, Gurbuxani S, Mullally A, Levine RL, Tefferi A, Crispino JD. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nature Medicine. 2015 Dec;21(12):1473-80. 

14. Krönke J*, Fink EC*, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND,  Chamberlain PP, Mani DR,  Wah Man H, Gandhi AK, Svinkina T, Schneider RK, McConkey M, Järås M, Griffiths E, Wetzler M, Bullinger L, Cathers BE, Carr SA, Chopra R, and Ebert BL. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015 July 9;523(7559):183-8. 

15. Kramann R, Fleig SV, Schneider RK, Fabian SL, DiRocco DP, Maarouf M, Wongboonsin J, Ikeda Y, Heckl D, Chang SL, Rennke HG, Waikar SS, Humphreys BD Pharmacological Gli2 Inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. Journal of Clinical Investigation 2015 Aug 3;125(8):2935-51.

16. Schneider RK, Ademà V, Heckl D, Järås M, Mallo M, Lord AM, Chu LP, McConkey ME, Kramann R, Mullally A, Bejar R, Solé F, Ebert BL. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014 Oct 13;26(4):509-20. 

17. Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, Henderson JM, Ebert BL and Humphreys BD. Perivascular Gli1+ Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis. Cell Stem Cell. November 2014. 

18. Chen E, Schneider RK, Breyfogle LJ, Rosen EA, Poveromo L, Elf S, Ko A, Brumme K, Levine R, Ebert BL, Mullally A. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms. Blood. 2014 Jan 8;125(2):327-35. 

19. Losman JA, Looper R, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley G, Root D, Ebert BL, Kaelin WG Jr. (R)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible. Science. 2013, March 29;339(6127):1621-5. 

20. Mullally A, Poveromo L, Schneider RK, Al-Shahrour F, Lane SW, Ebert BL. Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F polycythemia vera. Blood. 2012 Jul 5;120(1):166-72. 

Bella Banjanin, MD, MSc
Inge Snoeren, MSc
Hélène Gleitz, PhD, Assistand Professor
Stijn Fuchs, BSc
Stephani Schmitz, MSc