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Hartmann Laboratory

Microenvironment-induced therapy resistance in leukemia and lymphoma

Scientific focus

Our group is interested in how the tumor microenvironment mediates therapy resistance in leukemia and lymphoma. In particular, we address how adhesive ligands, cytokines and antigens affect the capacity of integrins to mediate tumor cell retention in protective niches. We mainly focus on the pathophysiological role of VLA-4 integrin activation in chronic lymphocytic leukemia and other hematopoietic malignancies.

 

Team

Principal Investigator

PD Dr. rer. nat. Tanja Nicole Hartmann

+49 (0) 761 270 71511

tanja.hartmann@uniklinik-freiburg.de


Dr. Lixia Li

Dr. rer. nat. Lixia Li
Postdoctoral scientist

+49 (0) 761 270 71800

lixia.li@uniklinik-freiburg.de

Dr. rer. nat. Svenja Dannewitz-Prosseda
Postdoctoral scientist

svenja.dannewitz@uniklinik-freiburg.de

Laura Polcik

Laura Polcik
PhD student

+49 (0) 761 270 71800

laura.polcik@uniklinik-freiburg.de

Danielle-Justine Danner

Danielle-Justine Danner
Technician, MD student

+49 (0) 761 270 71920

danielle.danner@uniklinik-freiburg.de

Driti Ashok
PhD student

+49 (0) 761 270 71920

driti.ashok@uniklinik-freiburg.de

Frederic Spatafora
Bachelor student

frederic.spatafora@uniklinik-freiburg.de

Susanne Reinfeld
MD student

+49 (0) 761 270 71920

susanne.reinfeld@uniklinik-freiburg.de

Katinka Hartnegg
MD Student

+49 (0) 761 270 71920

katinka.hartnegg@uniklinik-freiburg.de

Jennifer Schönbeck
Master student

jennifer.schoenbeck@uniklinik-freiburg.de

Sophia Engel
Student apprentice

+49 761 270 71920

sophia.engel@uniklinik-freiburg.de

Highlights of our new publication in JLB:

Kindlin-3 puts the brakes on B cell activation and differentiation.

Justement LB. J Leukoc Biol. 2022 Apr;111(4):741-743. doi: 10.1002/JLB.1CE1121-597R. Epub 2022 Feb 3.

Highlighting Editorial zu:

Härzschel A, Li L, Krenn PW, Szenes-Nagy E, Andrieux G, Bayer E, Pfeifer D, Polcik L, Denk U, Höpner JP, Karabatak E, Danner DJ, Tangermann S, Kenner L, Jumaa H, Greil R, Börries M, Ruppert R, Maity PC, Hartmann TN. J Leukoc Biol. 2022 Apr;111(4):745-758. doi: 10.1002/JLB.1HI0621-313R. Epub 2021 Dec 10.

New Frontiers Research Topic

Metabolism and Cell Adhesion in Cancer is a new article that will add to our continuing efforts to understand the intricate relationship between cell metabolism, oncogenesis and adhesion.

Our previous data suggest that the leukemia cell-stroma interface may bear signaling hubs that integrate oncogenic signals and protective cues from the tumor microenvironment. Current projects study the impact of these adhesive interfaces in the context of disease progression and therapy resistance in chronic lymphocytic leukemia (CLL), acute myeloid leukemia and multiple myeloma. We are particularly interested on activation of the VLA-4 integrin by different signals derived from the hematopoietic microenvironment. We use time-lapse and real-time microscopy, flow cytometric tools combined with immunofluorescence and mouse models to characterize the contribution of adhesion to therapy resistance against novel kinase inhibitors.

Leukemia cells interact with stromal cells. This VLA-4 mediated interaction supplies the tumor cell with crucial survival and proliferation signals and eventually therapy resistance.

Different ways of integrin activation are involved in chronic lymphocytic leukemia and acute myeloid leukemia. In chronic lymphocytic leukemia, inside-out activation of the VLA-4 integrin (also known as CD29/CD49d) occurs upon antigen or chemokine stimulation in secondary lymphoid organs and involves several kinases. Expression of CD49d in this disease marks a high-risk group because this interaction contributes to therapy resistance.

In acute myeloid leukemia, CD44 critically contributes to VLA-4 activation in the bone marrow environment involving Src and other kinases.

Full publication list see: https://pubmed.ncbi.nlm.nih.gov/?term=Hartmann%20TN&page=6

Selected publications of last two years:

  1. Editorial: Metabolism and Cell Adhesion in Cancer.
    Hartmann TN. Front Cell Dev Biol. 2022
  2. Insights Into Bone Marrow Niche Stability: An Adhesion and Metabolism Route.
    Ashok D, Polcik L, Dannewitz Prosseda S, Hartmann TN. Front Cell Dev Biol. 2022
  3. Ex vivo propagation in a novel 3D high-throughput co-culture system for multiple myeloma.
    Waldschmidt JM, Fruttiger SJ, Wider D, Jung J, Thomsen AR, Hartmann TN, Duyster J, Hug MJ, Azab KA, Jung M, Wäsch R, Engelhardt M. J Cancer Res Clin Oncol. 2022
  4. Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation.
    Härzschel A, Li L, Krenn PW, Szenes-Nagy E, Andrieux G, Bayer E, Pfeifer D, Polcik L, Denk U, Höpner JP, Karabatak E, Danner DJ, Tangermann S, Kenner L, Jumaa H, Greil R, Börries M, Ruppert R, Maity PC, Hartmann TN. J Leukoc Biol. 2022
  5. Elastin MIcrofibriL INterfacer1 (EMILIN-1) is an alternative prosurvival VLA-4 ligand in chronic lymphocytic leukemia.
    Tissino E, Pivetta E, Capuano A, Capasso G, Bomben R, Caldana C, Rossi FM, Pozzo F, Benedetti D, Boldorini R, Gaidano G, Rossi D, Zamò A, Hartmann TN, Doliana R, Colombatti A, Gattei V, Spessotto P, Zucchetto A. Hematol Oncol. 2022
  6. CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues.
    Yu X, Munoz-Sagredo L, Streule K, Muschong P, Bayer E, Walter RJ, Gutjahr JC, Greil R, Concha ML, Müller-Tidow C, Hartmann TN, Orian-Rousseau V. Blood. 2021
  7. CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity
    Gutjahr JC, Bayer E, Yu X, Laufer JM, Höpner JP, Tesanovic S, Härzschel A, Auer G, Rieß T, Salmhofer A, Szenes E, Haslauer T, Durand-Onayli V, Ramspacher A, Pennisi SP, Artinger M, Zaborsky N, Chigaev A, Aberger F, Neureiter D, Pleyer L, Legler DF, Orian-Rousseau V, Greil R, Hartmann TN.
    Haematologica. 2020
  8. VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects
    Härzschel A, Zucchetto A, Gattei V, Hartmann TN.
    Int J Mol Sci. 2020
  9. TCL1 transgenic mice as a model for CD49d-high chronic lymphocytic leukemia
    Szenes E, Härzschel A, Decker S, Tissino E, Pischeli J, Gutjahr JC, Kissel S, Pennisi S, Höpner JP, Egle A, Zaborsky N, Dierks C, Follo M, Chigaev A, Zucchetto A, Greil R, Gattei V, Hartmann TN.
    Leukemia 2020
  10. CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression
    Tissino E, Pozzo F, Benedetti D, Caldana C, Bittolo T, Rossi FM, Bomben R, Nanni P, Chivilò H, Cattarossi I, Zaina E, Norris K, Polesel J, Gentile M, Tripepi G, Moia R, Santinelli E, Innocenti I, Olivieri J, D'Arena G, Laurenti L, Zaja F, Pozzato G, Chiarenza A, Di Raimondo F, Rossi D, Pepper C, Hartmann TN, Gaidano G, Del Poeta G, Gattei V, Zucchetto A.
    Blood 2020