PhD Scientific Days 2020

Pathology and Oncology II. Posters

Phenotypic Changes in CLL Cells in a Patient Acquiring Venetoclax Resistance

Előadó neve

Dr. Takács, Ferenc

Előadó munkahelye

I. Department of Pathology and Experimental Cancer Research

Előadó telefonszáma

+36307430305

Előadó e-mail címe

takacs.ferenc@med.semmelweis-univ.hu

Az előadás címe

Phenotypic Changes in CLL Cells in a Patient Acquiring Venetoclax Resistance

Szerző(k) neve és munkahelye

1 Ferenc Takács 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
2 Gábor Mikala South-Pest Central Hospital- National Institute of Hematology and Infectology, Budapest
3 Dóra Aczél MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest
4 Andrea Reszegi 1st Department of Pathology and Experimental Cancer Research-Molecular Pathology Research Group
5 Ágnes Czeti 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
6 Donát Alpár MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest
7 Csaba Bödör MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest
8 Gábor Szalóki 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
9 Ilona Kardos 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
10 Gábor Barna 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest

Szekció

Pathology and Oncology II. Posters

Language of the presentation

English

Section, first choice

Pathology and Oncology

Section, second choice

Clinical Medicine

Összefoglaló szövege

Introduction: Chronic lymphoid leukemia (CLL) is the most common adult leukemia in the western world, CLL is a indolent and biologically heterogeneous disease. New targeted therapies including the selective Bcl-2 inhibitor venetoclax were introduced in recent years. Although venetoclax is a highly effective drug but acquired drug resistance may make the long-term treatment challenging.
Aims Our aim was to investigate the signal transduction and immunophenotypic changes in a patient who developed acquiring venetoclax resistance. Furthermore, we compared the phenotype of resistant CLL cells in bone marrow and peripheral blood.
Method: We collected peripheral blood (PB) samples at the time of initiation of venetoclax therapy and on 180th, 270th, 360th, and 450th day of treatment. Furthermore, PB and bone marrow (BM) samples were available at the time of overt clinical resistance (450th day). Cell surface molecules CD49d, CD38, ROR1, CD69, CD86, CD27, CD184 and CD185 were measured by flow cytometry. We also investigated the most common Bcl-2 resistance mutation (G101V) by digital droplet PCR. Protein and apoptosis arrays were performed from PB samples on the day 0 and the day 360 of venetoclax therapy, and from PB and BM samples at the onset of resistance.
Results: We observed that the expression of surface markers CD184, CD185 and CD86 decreased during venetoclax therapy until the onset of the resistance. CD69 and ROR1 showed bimodal distribution. Higher CD69 expression was in BM and CD185 expression was higher in PB. The G101V Bcl-2 resistance mutation was not detected in any of the samples analysed. Levels of BAD, BAX, XIAP, Bcl-XL and, p-CREB proteins were elevated during therapy and decreased at the time of venetoclax resistance. Expression levels of Bcl-2 decreased during the therapy, however in the resistance sample the Bcl-2 expression was higher compared to the initial presentation. In the BM sample XIAP, Bcl-XL, and p-CREB expression levels were higher compared to the PB sample at the time of resistance.
Conclusions: Based on our results, development of venetoclax resistance is associated with changes in expression of surface proteins and phospho-proteins in CLL cells. Monitoring of these markers (CD185, Bcl-2, XIAP and p-CREB) by flow cytometry during the disease course may be helpful in the early detection of acquired venetoclax resistance.

Additional Information

Supervisor's name: Gábor Barna
E-mail adress: barna.gabor@med.semmelweis-univ.hu

Supporting grants: EFOP-3.6.3-VEKOP-16-2017-00009, NVKP_16-1-2016-0004; NKFIH K16-119950, KH17-126718 and ÚNKP-19-3-I-SE-33, ÚNKP-19-4-SE-77; HAS LP95021; János Bolyai Scholarship Program; Scholarship For The Young Talents of The Nation NTP-NFTÖ-18-B-0165

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

4661

Start

12:56

End

12:59

Authors (legacy)

1 Ferenc Takács 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
2 Gábor Mikala South-Pest Central Hospital- National Institute of Hematology and Infectology, Budapest
3 Dóra Aczél MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest
4 Andrea Reszegi 1st Department of Pathology and Experimental Cancer Research-Molecular Pathology Research Group
5 Ágnes Czeti 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
6 Donát Alpár MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest
7 Csaba Bödör MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Budapest
8 Gábor Szalóki 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
9 Ilona Kardos 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest
10 Gábor Barna 1st Department of Pathology and Experimental Cancer Research Flow Cytometryc Research Group, Budapest