CLINICAL VALIDATION OF ANKRD36 MUTATIONS AS A NOVEL BIOMARKER FOR MONITORING EARLY PROGRESSION AND TIMELY CLINICAL INTERVENTIONS IN BLAST CRISIS CML
Main Article Content
Keywords
Chronic Myeloid Leukemia, CML progression, Poor survival, Genomic instability, Blast crisis, ANKRD36, Clinical validation
Abstract
Background: Chronic Myeloid Leukemia (CML) is initiated in the bone marrow due to the chromosomal translocation t(9;22), resulting in the fusion oncogene BCR-ABL. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL have transformed fatal CML into an almost curable disease. However, TKIs lose efficacy during disease progression, and the mechanism of CML progression remains to be fully understood. Additionally, common molecular biomarkers for CML progression are lacking. Our studies previously detected ANKRD36 (c.1183_1184 delGC and c.1187_1188 dupTT) associated exclusively with advanced phase CML. However, clinical validation of this finding was pending. Therefore, this study aimed to clinically validate mutated ANKRD36 as a novel biomarker of CML progression.
Materials and Methods: The study enrolled 124 patients in all phases of CML, recruited from Mayo Hospital and Hameed Latif Hospital in Lahore, Punjab, between January 2019 and August 2021. All response criteria were adopted from the European LeukemiaNet guideline 2020. Informed consent was obtained from all study subjects. The study was approved by scientific and ethical review committees of all participating centers.
Sanger sequencing was employed to detect ANKRD36 mutations in CML patients in accelerated phase (AP) (n=11) and blast crisis (BC) (n=10), with chronic-phase CML (CP-CML) patients as controls (n=103). Samples were processed using Big Dye Terminator Cycle Sequencing Ready Reaction kits and sequenced using ABI Prism 3730 Genetic Analyzer, and sequencing using forward and reverse primers for ANKRD36.
Results: During our study, 17% of CML patients progressed to advanced phases AP-CML n= 11 (8.9%) and BC-CML n=10 (8.1%). The chronic- and advanced-phase patients showed significant difference with respect to male-to-female ratio, hemoglobin level, WBC count, and platelet count. Sanger sequencing detected ANKRD36 mutations c.1183_1184 delGC and c.1187_1185 dupTT exclusively in all AP- and BC-CML patients but in none of the CP-CML patients. Nevertheless, mutations status was not associated with male-to-female ratio, hemoglobin level, WBC count, and platelet count, which makes ANKRD32 as an independent predictor of early and terminal disease progression in CML.
Conclusions: The study confirms ANKRD36 as a novel genomic biomarker for early and late CML progression. Further prospective studies should be carried out in this regard. ANKRD36, although fully uncharacterized in humans, shows the highest expression in bone marrow, particularly myeloid cells. Functional integrated genomic studies are recommended to further explore the role of ANKRD36 in the biology and pathogenesis of CML.
References
2. Cong, T., Liu, G.X., Cui, J.X., Zhang, K.C., Chen, Z.D., Chen, L., Wei, B. and Huang, X.H. (2018). [Exome sequencing of gastric cancers screened the differences of clinicopathological phenotypes between the mutant and the wide-type of frequently mutated genes]. Zhonghua Yi Xue Za Zhi, 98(28), pp.2242–2245.
3. Cross, N.C.P., Ernst, T., Branford, S., Cayuela, J.-M., Deininger, M., Fabarius, A., Kim, D.D.H., Machova Polakova, K., Radich, J.P., Hehlmann, R., Hochhaus, A., Apperley, J.F. and Soverini, S. (2021). European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia. Leukemia, [online] 37(11), pp.2150–2167.
4. Emine Merve Savaş, Seda Güleç Yılmaz, Ayşe Asena Başer Dikyar, Zübeyde Nur Özkurt, Ramazan Öcal, Can, F., Sezgin Pepeler, Lale Aydın Kaynar, Sanem Gökçen, Abdülkerim Yıldız, Murat Albayrak, Sema Karakuş, Özcan Çeneli̇ and Münci Yağcı (2021). Long-term Results of Imatinib Discontinuation in Patients with Chronic-phase Chronic Myeloid Leukemia: A National Multicenter Prospective Study. Turkish journal of hematology, [online] 40(4), pp.236–241.
5. Fagerberg, L., Hallström, B.M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., Habuka, M., Tahmasebpoor, S., Danielsson, A., Edlund, K., Asplund, A., Sjöstedt, E., Lundberg, E., Szigyarto, C.A.-K., Skogs, M., Takanen, J.O., Berling, H., Tegel, H., Mulder, J. and Nilsson, P. (2013). Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics. Molecular & Cellular Proteomics, 13(2), pp.397–406.
6. Fang, Y., Wang, X., Li, W., Han, J., Jin, J., Su, F., Zhang, J., Huang, W., Xiao, F., Pan, Q. and Zou, L. (2018). Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus. International Journal of Molecular Medicine.
7. Gleixner, K.V., Filik, Y., Berger, D., Schewzik, C., Stefanzl, G., Sadovnik, I., Degenfeld-Schonburg, L., Eisenwort, G., Schneeweiss-Gleixner, M., Byrgazov, K., Sperr, W.R., Mayer, J., Lion, T. and Valent, P. (2021). Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1T315I-compound mutations. American journal of cancer research, 11(9), pp.4470–4484.
8. Hochhaus, A., Baccarani, M., Silver, R.T., Schiffer, C., Apperley, J.F., Cervantes, F., Clark, R.E., Cortes, J.E., Deininger, M.W., Guilhot, F., Hjorth-Hansen, H., Hughes, T.P., Janssen, J.J.W.M., Kantarjian, H.M., Kim, D.W., Larson, R.A., Lipton, J.H., Mahon, F.X., Mayer, J. and Nicolini, F. (2020). European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia, 34.
9. Höglund, M., Sandin, F. and Simonsson, B. (2015). Epidemiology of chronic myeloid leukaemia: an update. Annals of Hematology, 94(S2), pp.241–247.
10. Iqbal, Z., Absar, M., Akhtar, T., Aleem, A., Jameel, A., Basit, S., Ullah, A., Afzal, S., Ramzan, K., Rasool, M., Karim, S., Mirza, Z., Iqbal, M., AlMajed, M., AlShehab, B., AlMukhaylid, S., AlMutairi, N., Al-anazi, N., Sabar, M.F. and Arshad, M. (2021). Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia. Biology, 10(11), p.1182
11. Jacquet, L., Wood, V., Kadeva, N., Cornwell, G., Codognotto, S., Stephenson, E. and Ilic, D. (2016). Generation of KCL040 clinical grade human embryonic stem cell line. Stem Cell Research, 16(1), pp.173–176.
12. Jain, P., Kantarjian, H., Alattar, M.L., Jabbour, E., Sasaki, K., Gonzalez, G.N., Dellasala, S., Pierce, S., Verstovsek, S., Wierda, W., Borthakur, G., Ravandi, F., O’Brien, S. and Cortes, J. (2015). Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials. The Lancet Haematology, 2(3), pp.e118–e128.
13. Ji Eun Shin, Kim, S., Kong, M., Kim, H.-R., Yoon, S.-M., Kee, K., Jung Ah Kim, Dong Hyeon Kim, So Yeon Park, Jae Hyung Park, Kim, H., Kyoung Tai No, Lee, H.-W., Heon Yung Gee, Hong, S., Guan, K., Roe, J., Lee, H., Dong Wook Kim and Hyun Woo Park (2021). Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia. Molecular Cancer, [online] 22(1).
14. Jonathan Dennis Rodriguez, Iniguez, A., Jena, N., Tata, P., Liu, J., Lander, A.D., Lowengrub, J. and Richard Van Etten (2021). Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy. eLife, [online] 12.
15. Ke, J., Kang, L., Jiang, A. and Zhao, Q. (2021). Development and Validation of a Diagnostic Model Based on Hypoxia-Related Genes in Myocardial Infarction. International Journal of General Medicine, [online] Volume 16, pp.2111–2123.
16. Nittaya Limsuwanachot, Budsaba Rerkamnuaychoke, Pimjai Niparuck, Roongrudee Singdong, Adcharee Kongruang, Piyapha Hirunpatrawong, Thanaporn Siriyakorn, Pa-thai Yenchitsomanus and Teerapong Siriboonpiputtana (2021). A customized mass array panel for BCR::ABL1 tyrosine kinase domain mutation screening in chronic myeloid leukemia. 28, pp.122–132.
17. Ono, T., Takahashi, N., Kizaki, M., Kawaguchi, T., Suzuki, R., Yamamoto, K., Ohnishi, K., Naoe, T. and Matsumura, I. (2021). Clinical outcomes of second-generation tyrosine kinase inhibitors versus imatinib in older patients with CML. Cancer Science, 114(3), pp.995–1006.
18. Pajiep, M., Conte, C., Huguet, F., Gauthier, M., Despas, F. and Lapeyre-Mestre, M. (2021). Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France. Frontiers in Oncology, 11.
19. Pan, S., Li, Z., Wang, Y., Liang, L., Liu, F., Qiao, Y., Li, D. and Liu, Z. (2021). A comprehensive weighted gene co-expression network analysis uncovers potential targets in diabetic kidney disease. Journal of Translational Internal Medicine, 10(4), pp.359–368.
20. Perilli, L., Tessarollo, S., Albertoni, L., Curtarello, M., Pastò, A., Brunetti, E., Fassan, M., Rugge, M., Indraccolo, S., Amadori, A., Bortoluzzi, S. and Zanovello, P. (2019). Silencing of miR-182 is associated with modulation of tumorigenesis through apoptosis induction in an experimental model of colorectal cancer. BMC Cancer, 19(1).
21. Rinaldi, I. and Winston, K. (2021). Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review. Journal of Blood Medicine, [online] Volume 14, pp.261–277.
22. Rudich, A., Garzon, R. and Dorrance, A. (2021). Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance. International Journal of Molecular Sciences, 23(20), p.12271.
23. Soverini, S. (2021). Resistance mutations in CML and how we approach them. Hematology, [online] 2021(1), pp.469–475.
24. Szabo, S.M., Levy, A.R., Davis, C., Holyoake, T.L. and Cortes, J. (2010). A Multinational Study of Health State Preference Values Associated with Chronic Myelogenous Leukemia. Value in Health, 13(1), pp.103–111.
25. Yamada, Y., Aoki, T., Kojima, S., Sugawara, S., Kato, M., Atsushi Okato, Yamazaki, K., Naya, Y., Ichikawa, T. and Seki, N. (2018). Regulation of antitumor miR‐144‐5p targets oncogenes: Direct regulation of syndecan‐3 and its clinical significance. Cancer Science, 109(9), pp.2919–2936.
26. Yan, Y., Wang, J., Yu, L., Cui, B., Wang, H., Xiao, X., Zhang, Y., Zheng, J., Wang, J., Hui, R. and Wang, Y. (2021). ANKRD36 Is Involved in Hypertension by Altering Expression of ENaC Genes. Circulation Research, 129(11), pp.1067–1081.
27. Wang, L., Li, L., Chen, R., Huang, X. and Ye, X. (2021). Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients. Cancer Management and Research, Volume 13, pp.4987–5000.
28. Zhang, B., Zhao, D., Chen, F., Frankhouser, D., Wang, H., Pathak, K.V., Dong, L., Torres, A., Krystine Garcia-Mansfield, Zhang, Y., Dinh Hoa Hoang, Chen, M.-H., Shu, T., Cho, H., Liang, Y., Perrotti, D., Branciamore, S., Rockne, R.C., Wu, X. and Ghoda, L. (2021). Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis. Nature Communications, [online] 14(1).
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Muhammad Absar
Department of Pathology & Laboratory Medicine, King Abdulaziz Hospital National Guard, AlAhsa - Saudi Arabia
Nawaf Alanazi
Department of Pediatrics, King Abdulaziz Hospital, Al-Ahsa - Saudi Arabia
Abdulaziz Siyal
Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Masood Shammas
Dana Farbar Cancer Institute, University of Harvard, Boston - USA
Amer Mahmood
Department of Pediatrics, King Abdulaziz Hospital, Al-Ahsa - Saudi Arabia
Sulman Basit
Centre for Genetics and Inherited Diseases, Taibah University Madinah - Kingdom of Saudi Arabia
Sarah AlMukhaylid
Genomic Medicine & Oncology/Hematology Group, Quality Assurance & Accreditation Unit (QAAA Unit), CoAMS-A/CLSP, King Saud Bin Abdulaziz University for Health Sciences & King Abdullah International Medical Research Centre (KAIMRC) / SSBMT, King Abdulaziz Medical City, National Guard Health Affairs, Al-Ahsa - Saudi Arabia
Hematology, Oncology & Pharmacogenetic Engineering Sciences (HOPES) Group, Department of Zoology, Univ. of Punjab, Pakistan (King Saud Bin Abdulaziz Univ.), Lahore - Pakistan
Zafar Iqbal
Pakistan Society for Molecular and Clinical Hematology, Lahore - Pakistan
Centre for Applied Molecular Biology (CAMB), University of the Punjab, Lahore – Pakistan.