In the last few years, the standard of care for CLL has changed from chemotherapy to targeted agents. First-line therapy uses specific inhibitors of BCL2 or Bruton's tyrosine kinase (BTK) in combination with monoclonal antibodies (Ab) against CD202. The elucidation of potential resistance mechanisms to these substances is therefore of great importance.

The key hypothesis of this application is based on the premise that signals of the tumor microenvironment (TME) can modify CLL cells to generate resistance to inhibitor therapy. N New in vivo models with conditional expression of human BCL2 and CD20 in malignant B cell will allow us to study clinically active drugs.

We will investigate primary CLL samples upon inhibitor treatment, and we will characterize the composition of TME and CLL cells upon resistance against combination therapies. Moreover, we aim to identify factors in myeloid cells that mediate and support BCL2 inhibitor resistance in CLL cells. Altogether, our overall aim is to investigate the dialogue between CLL cells and the TME as a key mechanism for resistance against novel inhibitor combinations (see figure).

Clinical Relevance

CLL is the most common leukemia in the Western world and the majority of patients is still not cured until today. Since survival CLL cells strongly depends on cellular and chemical interactions within its TME, we will investigate the role of specific TME stimuli in mediating resistance to targeted agents such as αCD20Ab/BCL2i/BTKi, which are in current clinical use. Finally, we aim to identify novel treatment options to overcome resistance against combinations of targeted agents.

Approach

CLL in vivo modelling
macrophages
BCL2 family members

Lab Website

For more information, please check Dr. Frenzel´s and Prof. Halleks websites.

Affiliations - Lukas Frenzel

Affiliations - Michael Hallek

Publication Record on PubMed - Lukas Frenzel

Publication Record on PubMed - Michael Hallek

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024

Beielstein AC, Izquierdo E, Blakemore S, Nickel N, Michalik M, Chawan S, Brinker R, Bartel HH, Vorholt D, Albert L, Nolte JL, Linke R, Costa Picossi CR, Sáiz J, Picard F, Florin A, Meinel J, Büttner R, Diefenhardt P, Brähler S, Villaseñor A, Winkels H, Hallek M, Krüger M, Barbas C, Pallasch CP. Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition. Cell Rep Med. 2024 Dec 17;5(12):101830. doi: 10.1016/j.xcrm.2024.101830. Epub 2024 Nov 26. PMID: 39603243; PMCID: PMC11722127.
Jestrabek H, Kohlhas V, Hallek M, and Nguyen PH (2024). Impact of leukemia-associated macrophages on the progression and therapy response of chronic lymphocytic leukemia. Leuk Res143, 107531. doi:10.1016/j.leukres.2024.107531.
Lewis RI, Vom Stein AF, Hallek M. Targeting the tumor microenvironment for treating double-refractory chronic lymphocytic leukemia. Blood. 2024 Aug 8;144(6):601-614. doi: 10.1182/blood.2023022861. PMID: 38776510.
Meder L, Orschel CI, Otto CJ, Koker M, Bragelmann J, Ercanoglu MS, Dahling S, Compes A, Selenz C, Nill M, Dietlein F, Florin A, Eich ML, Borchmann S, Odenthal M, Blazquez R, Hilberg F, Klein F, Hallek M, Buttner R, Reinhardt HC, and Ullrich RT (2024). Blocking the angiopoietin-2-dependent integrin beta-1 signaling axis abrogates small cell lung cancer invasion and metastasis. JCI Insight9. doi:10.1172/jci.insight.166402.
Pacholewska A, Lienhard M, Brüggemann M, Hänel H, Bilalli L, Königs A, Heß F, Becker K, Köhrer K, Kaiser J, Gohlke H, Gattermann N, Hallek M, Herling CD, König J, Grimm C, Herwig R, Zarnack K, Schweiger MR. Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects of SF3B1 mutations. Genome Res. 2024 Nov 20;34(11):1832-1848. doi: 10.1101/gr.279327.124. PMID: 39271291; PMCID: PMC11610591.
vom Stein AF, Hallek M and Nguyen PH (2024). Role of the tumor microenvironment in CLL pathogenesis. Semin Hematol 61(3): 142-154.
von Jan J, Timonen S, Braun T, Jiang Q, Ianevski A, Peng Y, McConnell K, Sindaco P, Müller TA, Pützer S, Klepzig H, Jungherz D, Dechow A, Wahnschaffe L, Giri AK, Kankainen M, Kuusanmäki H, Neubauer HA, Moriggl R, Mazzeo P, Schmidt N, Koch R, Hallek M, Chebel A, Armisen D, Genestier L, Bachy E, Mishra A, Schrader A, Aittokallio T, Mustjoki S, Herling M. Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses. Blood. 2024 Oct 10;144(15):1595-1610. doi: 10.1182/blood.2023022884. PMID: 38941598.

2023

de Oliveira TD, Vom Stein A, Rebollido-Rios R, Lobastova L, Lettau M, Janssen O, Wagle P, Nguyen PH, Hallek M, and Hansen HP (2023). Stromal cells support the survival of human primary chronic lymphocytic leukemia (CLL) cells through Lyn-driven extracellular vesicles. Front Med (Lausanne) 9, 1059028. doi:10.3389/fmed.2022.1059028.
Flumann R, Hansen J, Pelzer BW, Nieper P, Lohmann T, Kisis I, Riet T, Kohlhas V, Nguyen PH, Peifer M, Abedpour N, Bosco G, Thomas RK, Kochanek M, Knufer J, Jonigkeit L, Beleggia F, Holzem A, Buttner R, Lohneis P, Meinel J, Ortmann M, Persigehl T, Hallek M, Calado DP, Chmielewski M, Klein S, Gothert JR, Chapuy B, Zevnik B, Wunderlich FT, von Tresckow B, Jachimowicz RD, Melnick AM, Reinhardt HC, and Knittel G (2023). Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies. Blood Cancer Discov 4, 78-97. doi:10.1158/2643-3230.BCD-22-0007.
Hassenruck F, Farina-Morillas M, Neumann L, Landini F, Blakemore SJ, Rabipour M, Alvarez-Idaboy JR, Pallasch CP, Hallek M, Rebollido-Rios R, and Krause G (2023). Functional impact and molecular binding modes of drugs that target the PI3K isoform p110delta. Commun Biol 6, 603. doi:10.1038/s42003-023-04921-z.
Jiang Q, Stachelscheid J, Bloehdorn J, Pacholewska A, Aszyk C, Grotenhuijs F, Muller T, Onder O, Wagle P, Herling CD, Kleppe M, Wang Z, Coombes KR, Robrecht S, Dalvi PS, Plosnita B, Mayer P, Abruzzo LV, Altmuller J, Gathof B, Persigehl T, Fischer K, Jebaraj B, Rienhoff HY, Ecker R, Zhao Y, Bruns CJ, Stilgenbauer S, Elenitoba-Johnson K, Hallek M, Schweiger MR, Odenthal M, Vasyutina E, and Herling M (2023). Oncogenic role and target properties of the lysine-specific demethylase KDM1A in chronic lymphocytic leukemia. Blood 142, 44-61. doi:10.1182/blood.2022017230.
Otte M, Stachelscheid J, Glass M, Wahnschaffe L, Jiang Q, Lone W, Ianevski A, Aittokallio T, Iqbal J, Hallek M, Huttelmaier S, Schrader A, Braun T, and Herling M (2023). The miR-141/200c-STAT4 Axis Contributes to Leukemogenesis by Enhancing Cell Proliferation in T-PLL. Cancers (Basel) 15. doi:10.3390/cancers15092527.
Simonis A, Kreer C, Albus A, Rox K, Yuan B, Holzmann D, Wilms JA, Zuber S, Kottege L, Winter S, Meyer M, Schmitt K, Gruell H, Theobald SJ, Hellmann AM, Meyer C, Ercanoglu MS, Cramer N, Munder A, Hallek M, Fatkenheuer G, Koch M, Seifert H, Rietschel E, Marlovits TC, van Koningsbruggen-Rietschel S, Klein F, and Rybniker J (2023). Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa. Cell 186, 5098-5113 e5019. doi:10.1016/j.cell.2023.10.002.
Stachelscheid J, Jiang Q, Aszyk C, Warner K, Bley N, Muller T, Vydzhak O, Symeonidis K, Crispatzu G, Mayer P, Blakemore SJ, Goehring G, Newrzela S, Hippler S, Robrecht S, Kreuzer KA, Pallasch C, Kruger M, Lechner A, Fischer K, Stilgenbauer S, Beutner D, Hallek M, Auguin D, Huttelmaier S, Bloehdorn J, Vasyutina E, and Herling M (2023). The proto-oncogene TCL1A deregulates cell cycle and genomic stability in CLL. Blood 141, 1425-1441.
Tzaridis T, Weller J, Bachurski D, Shakeri F, Schaub C, Hau P, Buness A, Schlegel U, Steinbach JP, Seidel C, Goldbrunner R, Schafer N, Wechsler-Reya RJ, Hallek M, Scheffler B, Glas M, Haeberle L, Herrlinger U, Coch C, Reiners KS, and Hartmann G (2023). A novel serum extracellular vesicle protein signature to monitor glioblastoma tumor progression. Int J Cancer 152, 308-319. doi:10.1002/ijc.34261.
Vom Stein AF, Rebollido-Rios R, Lukas A, Koch M, von Lom A, Reinartz S, Bachurski D, Rose F, Bozek K, Abdallah AT, Kohlhas V, Saggau J, Zolzer R, Zhao Y, Bruns C, Brockelmann PJ, Lohneis P, Buttner R, Haupl B, Oellerich T, Nguyen PH, and Hallek M (2023). LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1. Nat Commun 14, 1330. doi:10.1038/s41467-023-36824-2.

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