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Projects / Programmes source: ARIS

APOPTOSIS TARGETING OF LEUKEMIC CELLS IN CHRONIC MYELOID LEUKEMIA USING Cas9 – TargetCML9

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Research activity

Code Science Field Subfield
3.04.00  Medical sciences  Oncology   

Code Science Field
B490  Biomedical sciences  Haematology, extracellular fluids 

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
Crispr-CAS9, chronic myeloid leukemia, gene editing, induced apoptosis, hematopoietic stem cell transplant
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Researchers (17)
no. Code Name and surname Research area Role Period No. of publications
1.  35277  PhD Tina Fink  Biochemistry and molecular biology  Researcher  2019 - 2020  25 
2.  36426  PhD Anja Golob Urbanc  Biotechnology  Researcher  2019 - 2022  32 
3.  38164  Van Thai Ha  Pharmacy  Researcher  2020  12 
4.  06628  PhD Roman Jerala  Biochemistry and molecular biology  Researcher  2019 - 2022  1,189 
5.  52428  Sanjin Lulić    Technical associate  2020  0 
6.  53665  Špela Malenšek  Biochemistry and molecular biology  Researcher  2021 - 2022  17 
7.  21426  PhD Mateja Manček Keber  Pharmacy  Researcher  2019 - 2022  159 
8.  53568  Veronika Mikolič  Oncology  Junior researcher  2020 - 2022  17 
9.  23818  PhD Tadej Pajič  Human reproduction  Researcher  2019 - 2022  178 
10.  12684  PhD Helena Podgornik  Microbiology and immunology  Researcher  2019 - 2022  350 
11.  50616  Arne Praznik  Biochemistry and molecular biology  Researcher  2019  35 
12.  23126  PhD Irena Preložnik Zupan  Oncology  Researcher  2019 - 2022  418 
13.  35675  Urška Ribič    Technical associate  2019 - 2022  0 
14.  24908  PhD Matjaž Sever  Microbiology and immunology  Head  2019 - 2022  271 
15.  55061  Tina Strmljan    Technical associate  2021 - 2022  0 
16.  39364  Anže Verbič  Biochemistry and molecular biology  Technical associate  2019 - 2022  9 
17.  23817  PhD Samo Zver  Microbiology and immunology  Researcher  2019 - 2022  375 
Organisations (2)
no. Code Research organisation City Registration number No. of publications
1.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,422 
2.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,957 
Abstract
Chronic myeloid leukemia (CML) is a malignant disease resulting from neoplastic transformation of a hematopoietic stem cell. The underlining molecular mechanism behind CML onset is the formation of the BCR-ABL fusion gene caused by a translocation between chromosomes 9 and 22 (t(9;22)). The fusion gene transcript, an activated BCR-ABL1 kinase, plays an essential role in causing the vast majority of CML. Currently, CML is treated with selective tyrosine kinase inhibitors (TKI), which are generally well tolerated, although treatment is still associated with adverse events and represents a financial burden to patients and society. Targeting a unique genome sequence breakpoint not present in normal tissues using the CRISPR Cas9 system has been successfully exploited for research purposes on human prostate cancer and hepatocellular carcinoma cell lines, showing promising results 1, but has not been applied to hematologic malignancies. The goal of the proposed project is to implement a synthetic biology approach to the treatment of chronic myeloid leukemia. Since CML is caused by a well-defined chromosomal rearrangement, which is present in every CML patient, a gene editing strategy, targeted specifically to cancer cell gene rearrangements presents itself as an attractive strategy for the eradication of tumor burden in the host organism. The proposed strategy will first be tested on a constructed tumor cell line for the assessment of feasibility. Using a CRISPR Cas9 nickase, a suicide gene will be inserted specifically into tumor cells harboring the specific genomic rearrangement. Different modes of apoptosis activation will be tested and evaluated and in vivo functionality of the proposed therapeutic approach will be tested. In contrast to the currently available treatment strategies in CML, which are targeted against the product of the fusion gene that may acquire resistance mutations, our approach will be directed towards the fusion gene itself. As a final consequence it would enable elimination of cancer cells and ultimate healing. The proposed project represents a unique challenge in the field of hematology.
Significance for science
CRISPR-Cas9 editing of the genome has caused a revolution in the last several years in molecular genetics. Its application is seen in several fields including medicine and hematology where initial success was reported in conditions with single gene defects. Targeting malignant cells has not yet been performed in hematology. Also, improvement of apoptotic gene transfer has not been systematically addressed. If the project is successful, its translation to clinical application after extensive additional preclinical studies would be highly beneficial as it could lead to a cure for CML. This approach could avoid side effects of the currently available therapies and could improve quality of life of patients. Long term prospects of durable CML remission could be significantly improved in comparison to current approaches and it could be used to treat a large proportion of patients, if accompanied by analyses of specific characteristics of the patient’s cancer cells. By reducing the prevalence of patients with chronic therapy of CML the cost of disease treatment would be reduced. Developing a completely new treatment approach, using state-of-the art technology, would represent a great scientific advancement in CML treatment in Slovenia and elsewhere with the possibilities of transferring the method to other malignancies in hematology and solid tumors. CML is a perfect model neoplasm with clear primary genetic aberration which is directly responsible for the whole malignant process. Consequently, besides the exhaustive knowledge on genetic mechanisms, we also have all possible methods to follow disease progression and therapy efficiency. If the proposed approach would be successful, it could serve as a model to target cancer stem cells with a defined primary genetic events. This could be widely applicable not only in hematological malignancies but also in oncology in general.
Significance for the country
CRISPR-Cas9 editing of the genome has caused a revolution in the last several years in molecular genetics. Its application is seen in several fields including medicine and hematology where initial success was reported in conditions with single gene defects. Targeting malignant cells has not yet been performed in hematology. Also, improvement of apoptotic gene transfer has not been systematically addressed. If the project is successful, its translation to clinical application after extensive additional preclinical studies would be highly beneficial as it could lead to a cure for CML. This approach could avoid side effects of the currently available therapies and could improve quality of life of patients. Long term prospects of durable CML remission could be significantly improved in comparison to current approaches and it could be used to treat a large proportion of patients, if accompanied by analyses of specific characteristics of the patient’s cancer cells. By reducing the prevalence of patients with chronic therapy of CML the cost of disease treatment would be reduced. Developing a completely new treatment approach, using state-of-the art technology, would represent a great scientific advancement in CML treatment in Slovenia and elsewhere with the possibilities of transferring the method to other malignancies in hematology and solid tumors. CML is a perfect model neoplasm with clear primary genetic aberration which is directly responsible for the whole malignant process. Consequently, besides the exhaustive knowledge on genetic mechanisms, we also have all possible methods to follow disease progression and therapy efficiency. If the proposed approach would be successful, it could serve as a model to target cancer stem cells with a defined primary genetic events. This could be widely applicable not only in hematological malignancies but also in oncology in general.
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