Abstract
Kronik lenfositik lösemi (KLL) ileri yaş hastalarda en sık gözlenen lösemi türü olup, hem klinik hem de genetik açıdan oldukça heterojen bir hastalıktır. Kronik lenfositik lösemi de tekrarlayan kromozom anomalilerinin prognostik önemleri uzun yıllardır bilinmekte olup, gen mutasyonlarının da klinik önemleri açığa kavuşmaya başlamıştır. NOTCH1 gen mutasyonları KLL’de en sık mutasyon gözlenen gen olup, tedavi direnci ve Richter Sendromuna dönüşüm ile ilişkilendirilmektedir. Son yıllarda yapılan çalışmalarda NOTCH1 gen amplifikasyonları çeşitli kanser tiplerinde raporlanmıştır. Bizim daha önce izole delesyon 13q saptanan KLL vakaları ile yaptığımız bir çalışmada NOTCH1 gen dizisini içeren kopya sayısı artışları mikroarray yöntemi ile saptanmıştır ancak klinik bulgular ile ilişkilendirilmemiştir. Biz de bu çalışmamızda çeşitli kromozomal anomalilere sahip ve daha fazla KLL olgusuna ait periferik kan örneklerinde NOTCH1 gen kopya sayısı artışlarını FISH yöntemi ile incelemeyi ve KLL’nin klinik heterojenitesinde NOTCH1 amplifikasyonunun etkisini araştırmayı amaçladık. Çalışmaya dahil edilen 130 KLL vakasının 4’ünde FISH çalışması başarısızlıkla tamamlanmış olup, geriye kalan 126 olgunun hiçbirinde NOTCH1 gen kopya sayısı değişikliği tespit edilmemiştir. Çalışmamız sonucunda KLL’nin klinik heterojenitesinde NOTCH1 gen amplifikasyonlarının bir etkisi olmadığı sonucuna varılmıştır. Ancak olgu grubumuzun büyük kısmının, iyi prognostik etkiye sahip sitogenetik belirteçlere sahip olması sebebiyle, kötü klinik seyre sahip, daha fazla sayıda KLL vakalarında NOTCH1 gen kopya sayısının araştırılması gerekmektedir.
Keywords
Supporting Institution
Eskişehir Osmangazi Üniversitesi Bilimsel Araştırmalar Projeleri (BAP)
Project Number
TSA-2021-1668
References
- 1. Paul P, Stüssi G, Bruscaggin A, Rossi D. Genetics and epigenetics of CLL. Leuk Lymphoma. 2023;64:551-63.
- 2. Rodríguez D, Bretones G, Arango JR, Valdespino V, Campo E, Quesada V, et al. Molecular pathogenesis of CLL and its evolution. Int J Hematol. 2015;101:219-28.
- 3. Bosch F, Dalla-Favera R. Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol. 2019;16:684-701.
- 4. Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525-30.
- 5. Hernandez Tejada FN, Galvez Silva JR, Zweidler-McKay PA. The challenge of targeting notch in hematologic malignancies. Front Pediatr. 2014;2:54.
- 6. Rosati E, Baldoni S, De Falco F, Del Papa B, Dorillo E, Rompietti C, et al. NOTCH1 Aberrations in Chronic Lymphocytic Leukemia. Front Oncol. 2018;8:229.
- 7. Di Ianni M, Baldoni S, Del Papa B, Aureli P, Dorillo E, De Falco F, et al. NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells. Front Oncol. 2018;8:105.
- 8. Arruga F, Gizdic B, Serra S, Vaisitti T, Ciardullo C, Coscia M, et al. Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia. 2014;28:1060-70.
- 9. Baldoni S, Sportoletti P, Del Papa B, Aureli P, Dorillo E, Rosati E, et al. NOTCH and NF-κB interplay in chronic lymphocytic leukemia is independent of genetic lesion. Int J Hematol. 2013;98:153-7.
- 10. Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, et al. Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. Embo j. 1999;18:2803-11.
- 11. Arcaroli JJ, Tai WM, McWilliams R, Bagby S, Blatchford PJ, Varella-Garcia M, et al. A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer. Int J Cancer. 2016;138:195-205.
- 12. Cejkova P, Zettl A, Baumgärtner AK, Chott A, Ott G, Müller-Hermelink HK, et al. Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma. Virchows Arch. 2005;446:416-20.
- 13. Katarkar A, Bottoni G, Clocchiatti A, Goruppi S, Bordignon P, Lazzaroni F, et al. NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin. Nat Commun. 2020;11:5126.
- 14. Isik S, Gunden G, Gunduz E, Akay OM, Aslan A, Ozen H, et al. An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3. Cytogenet Genome Res. 2021;161:479-87.
- 15. Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96:1679-705.
- 16. Arruga F, Vaisitti T, Deaglio S. The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies. Front Oncol. 2018;8:550.
- 17. Xia Y, Huang CC, Dittmar R, Du M, Wang Y, Liu H, et al. Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer. Oncotarget. 2016;7:35818-31.
- 18. Pozzo F, Bittolo T, Tissino E, Zucchetto A, Bomben R, Polcik L, et al. Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond. Cancers (Basel). 2022;14(12).
- 19. Shaffer LG, Beaudet AL, Brothman AR, Hirsch B, Levy B, Martin CL, et al. Microarray analysis for constitutional cytogenetic abnormalities. Genet Med. 2007;9:654-62.
Abstract
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia observed in elderly patients and is a highly heterogeneous disease both clinically and genetically. The prognostic significance of recurrent chromosomal abnormalities in chronic lymphocytic leukemia has been known for many years, and the clinical significance of gene mutations has begun to emerge. NOTCH1 gene mutations are the most frequently mutated gene in CLL and are associated with treatment resistance and conversion to Richter Syndrome. In recent studies, NOTCH1 gene amplifications have been reported in various cancer types. In a study we conducted with CLL cases with isolated deletion 13q, copy number increases containing the NOTCH1 gene sequence were detected by microarray method, but they were not associated with clinical findings.In this study, we aimed to examine the NOTCH1 gene copy number increases in peripheral blood samples of more CLL cases with various chromosomal anomalies by FISH method and to investigate the effect of NOTCH1 amplification on the clinical heterogeneity of CLL. FISH study was completed unsuccessfully in 4 of 130 CLL cases included in the study, and NOTCH1 gene copy number changes were detected in any of the remaining 126 cases. As a result of our study, it was concluded that NOTCH1 gene amplifications have no effect on the clinical heterogeneity of CLL. However, since most of our case group has cytogenetic markers with good prognostic effect, it is necessary to investigate the NOTCH1 gene copy number in more CLL cases with poor clinical course.
Keywords
Project Number
TSA-2021-1668
References
- 1. Paul P, Stüssi G, Bruscaggin A, Rossi D. Genetics and epigenetics of CLL. Leuk Lymphoma. 2023;64:551-63.
- 2. Rodríguez D, Bretones G, Arango JR, Valdespino V, Campo E, Quesada V, et al. Molecular pathogenesis of CLL and its evolution. Int J Hematol. 2015;101:219-28.
- 3. Bosch F, Dalla-Favera R. Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol. 2019;16:684-701.
- 4. Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526:525-30.
- 5. Hernandez Tejada FN, Galvez Silva JR, Zweidler-McKay PA. The challenge of targeting notch in hematologic malignancies. Front Pediatr. 2014;2:54.
- 6. Rosati E, Baldoni S, De Falco F, Del Papa B, Dorillo E, Rompietti C, et al. NOTCH1 Aberrations in Chronic Lymphocytic Leukemia. Front Oncol. 2018;8:229.
- 7. Di Ianni M, Baldoni S, Del Papa B, Aureli P, Dorillo E, De Falco F, et al. NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells. Front Oncol. 2018;8:105.
- 8. Arruga F, Gizdic B, Serra S, Vaisitti T, Ciardullo C, Coscia M, et al. Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia. 2014;28:1060-70.
- 9. Baldoni S, Sportoletti P, Del Papa B, Aureli P, Dorillo E, Rosati E, et al. NOTCH and NF-κB interplay in chronic lymphocytic leukemia is independent of genetic lesion. Int J Hematol. 2013;98:153-7.
- 10. Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, et al. Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. Embo j. 1999;18:2803-11.
- 11. Arcaroli JJ, Tai WM, McWilliams R, Bagby S, Blatchford PJ, Varella-Garcia M, et al. A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer. Int J Cancer. 2016;138:195-205.
- 12. Cejkova P, Zettl A, Baumgärtner AK, Chott A, Ott G, Müller-Hermelink HK, et al. Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma. Virchows Arch. 2005;446:416-20.
- 13. Katarkar A, Bottoni G, Clocchiatti A, Goruppi S, Bordignon P, Lazzaroni F, et al. NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin. Nat Commun. 2020;11:5126.
- 14. Isik S, Gunden G, Gunduz E, Akay OM, Aslan A, Ozen H, et al. An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3. Cytogenet Genome Res. 2021;161:479-87.
- 15. Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96:1679-705.
- 16. Arruga F, Vaisitti T, Deaglio S. The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies. Front Oncol. 2018;8:550.
- 17. Xia Y, Huang CC, Dittmar R, Du M, Wang Y, Liu H, et al. Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer. Oncotarget. 2016;7:35818-31.
- 18. Pozzo F, Bittolo T, Tissino E, Zucchetto A, Bomben R, Polcik L, et al. Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond. Cancers (Basel). 2022;14(12).
- 19. Shaffer LG, Beaudet AL, Brothman AR, Hirsch B, Levy B, Martin CL, et al. Microarray analysis for constitutional cytogenetic abnormalities. Genet Med. 2007;9:654-62.
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Medical Genetics (Excl. Cancer Genetics) |
| Journal Section | ORİJİNAL MAKALE |
| Authors | |
| Project Number | TSA-2021-1668 |
| Publication Date | January 16, 2024 |
| Published in Issue | Year 2024 Volume: 46 Issue: 1 |