LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

Alexander F Vom Stein; Rocio Rebollido-Rios; Anna Lukas; Maximilian Koch; Anton von Lom; Sebastian Reinartz; Daniel Bachurski; France Rose; Katarzyna Bozek; Ali T Abdallah; Viktoria Kohlhas; Julia Saggau; Rebekka Zölzer; Yue Zhao; Christiane Bruns; Paul J Bröckelmann; Philipp Lohneis; Reinhard Büttner; Björn Häupl; Thomas Oellerich; Phuong-Hien Nguyen; Michael Hallek

doi:10.1038/s41467-023-36824-2

LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

Nat Commun. 2023 Mar 10;14(1):1330. doi: 10.1038/s41467-023-36824-2.

Authors

Alexander F Vom Stein^{1

2

3}, Rocio Rebollido-Rios^{1

2

3}, Anna Lukas^{1

2

3}, Maximilian Koch^{1

2

3}, Anton von Lom^{1

2

3

4}, Sebastian Reinartz^{1

2

3}, Daniel Bachurski^{1

2

3

4}, France Rose^{2

5}, Katarzyna Bozek^{2

3

5}, Ali T Abdallah³, Viktoria Kohlhas^{1

2

3}, Julia Saggau^{1

2

3}, Rebekka Zölzer^{1

2

3}, Yue Zhao⁶, Christiane Bruns⁶, Paul J Bröckelmann^{1

4

7}, Philipp Lohneis^{8

9}, Reinhard Büttner⁹, Björn Häupl^{10

11

12

13}, Thomas Oellerich^{10

11

12

13}, Phuong-Hien Nguyen^#^{14

15

16}, Michael Hallek^#^{17

18

19}

Affiliations

¹ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany.
² Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
³ CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
⁴ Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
⁵ University of Cologne, Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
⁶ Faculty of Medicine and University Hospital Cologne, Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
⁷ Max-Planck Institute for the Biology of Ageing, Cologne, Germany.
⁸ Reference Centre for Lymph Node Pathology and Hematopathology, Hämatopathologie Lübeck, Lübeck, Germany.
⁹ Faculty of Medicine and University Hospital Cologne, Department of Pathology, University of Cologne, Cologne, Germany.
¹⁰ Department of Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
¹¹ German Cancer Consortium (DKTK), Heidelberg, Germany.
¹² German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany.
¹⁴ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany. [email protected].
¹⁵ Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. [email protected].
¹⁶ CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. [email protected].
¹⁷ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany. [email protected].
¹⁸ Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. [email protected].
¹⁹ CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. [email protected].

^# Contributed equally.

Abstract

Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal fibroblasts to support leukemic progression. LYN is overexpressed in fibroblasts of lymph nodes of CLL patients. LYN-deficient stromal cells reduce CLL growth in vivo. LYN-deficient fibroblasts show markedly reduced leukemia feeding capacity in vitro. Multi-omics profiling reveals that LYN regulates the polarization of fibroblasts towards an inflammatory cancer-associated phenotype through modulation of cytokine secretion and extracellular matrix composition. Mechanistically, LYN deletion reduces inflammatory signaling including reduction of c-JUN expression, which in turn augments the expression of Thrombospondin-1, which binds to CD47 thereby impairing CLL viability. Together, our findings suggest that LYN is essential for rewiring fibroblasts towards a leukemia-supportive phenotype.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fibroblasts / metabolism
Gene Expression Regulation, Leukemic
Humans
Leukemia / genetics
Leukemia, Lymphocytic, Chronic, B-Cell* / genetics
Proto-Oncogene Proteins c-jun* / metabolism
Signal Transduction
Thrombospondins* / metabolism
src-Family Kinases* / metabolism

Substances

lyn protein-tyrosine kinase
src-Family Kinases
JUN protein, human
Proto-Oncogene Proteins c-jun
Thrombospondins