Published date: Dec 29 2023

Journal Title: Sudan Journal of Medical Sciences

Issue title: Sudan JMS: Volume 18 (2023), Issue No. 4

Pages: 525–538

DOI: 10.18502/sjms.v18i4.14741

Rabia Khalidrabiakhalid4ever950@gmail.comCentre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan

Sana RiasatInstitute of Microbiology and Molecular Genetics, University of the Punjab, Lahore

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease diagnosed in bone marrow, arising from a chromosomal translocation between chromosomes 9 and 22, resulting in the formation of fusion oncogene BCR–ABL. The product of this fusion oncogene is a new oncoprotein bcr–abl which possesses abnormal tyrosine kinase activity. In response to this, abnormal signaling pathway activation occurs, leading to cell transformation. BCR–ABL oncogene could be targeted by tyrosine kinase inhibitors (TKIs) to delay or inhibit the disease progression. Imatinib is the first drug designed against CML but resistance to this has led to the development of the second- and third generations of inhibitors that are active against many types of BCR–ABL gene mutations. However, somehow, due to disease progression, TKIs do not remain as effective. There are three well-characterized phases of CML: The chronic phase (CP), the accelerated phase, and the terminal stage which is the blast crisis (BC) stage. In the CP of CML, mature granulocytes and myeloid precursors become aggregated majorly in the bone marrow and peripheral blood. The accelerated phase is marked by increased disease severity and an increase in progenitor/precursor cell number. In the BC stage, undifferentiated blast cells grow in number. Many patients with CML are diagnosed during the CP of the disease, so the survival rate of CML is high. However, 20% of CML patients proceed to advanced stages that result in drug resistance, intolerance, and mortality. So, for proper CML treatment, drugs are needed to target multiple BCR– ABL mutations, delay or stop disease progression, and overcome resistance caused by BCR–ABL independent mechanisms, especially during advanced phases of CML. Moreover, drugs could be developed to eradicate the stem cells of CML. These targets could be achieved by understanding mechanisms of disease progression, disease relapse, and drug resistance by utilizing high throughput molecular genetics, cell biology and immunology techniques.

Keywords: CML, Philadelphia chromosome, BCR–ABL gene, blast crisis, leukemia

[1] Turgeon, M. L. (2005). Clinical hematology: Theory and procedures. Lippincott Williams & Wilkins.

[2] King, B., Trimarchi, T., Reavie, L., Xu, L., Mullenders, J., Ntziachristos, P., Aranda-Orgilles, B., Perez-Garcia, A., Shi, J., Vakoc, C., Sandy, P., Shen, S. S., Ferrando, A., & Aifantis, I. (2013). The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell, 153(7), 1552–1566. https://doi.org/10.1016/j.cell.2013.05.041

[3] Evans, D. G., Howard, E., Giblin, C., Clancy, T., Spencer, H., Huson, S. M., & Lalloo, F. (2010). Birth incidence and prevalence of tumor-prone syndromes: Estimates from a UK family genetic register service. American Journal of Medical Genetics. Part A, 152A(2), 327–332. https://doi.org/10.1002/ajmg.a.33139

[4] Jabbour, E., & Kantarjian, H. (2014). Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. American Journal of Hematology, 89(5), 547–556. https://doi.org/10.1002/ajh.23691

[5] Yang, Z. (2014). Molecular evolution: A statistical approach. Oxford University Press. https://doi.org/10.1093/acprof:oso/9780199602605.001.0001

[6] Druker, B. J., Guilhot, F., O’Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M. W., Silver, R. T., Goldman, J. M., Stone, R. M., Cervantes, F., Hochhaus, A., Powell, B. L., Gabrilove, J. L., Rousselot, P., Reiffers, J., Cornelissen, J. J., Hughes, T., Agis, H., . . . Larson, R. A., & the IRIS Investigators. (2006). Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. The New England Journal of Medicine, 355(23), 2408–2417. https://doi.org/10.1056/NEJMoa062867

[7] 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., Farooq Sabar, M….Mahmood, A. (2021). Integrated genomic analysis identifies ankrd36 gene as a novel and common biomarker of disease progression in chronic myeloid leukemia. Biology, 10(11), 1182.

[8] Klümper, T., Bruckmueller, H., Diewock, T., Kaehler, M., Haenisch, S., Pott, C., Bruhn, O., & Cascorbi, I. (2020). Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance. Experimental Hematology & Oncology, 9(1), 26. https://doi.org/10.1186/s40164-020-00183-1

[9] Hochhaus, A., Druker, B., Sawyers, C., Guilhot, F., Schiffer, C. A., Cortes, J., Niederwieser, D. W., Gambacorti-Passerini, C., Stone, R. M., Goldman, J., Fischer, T., O’Brien, S. G., Reiffers, J. J., Mone, M., Krahnke, T., Talpaz, M., & Kantarjian, H. M. (2008). Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment. Blood, 111(3), 1039–1043. https://doi.org/10.1182/blood-2007-07-103523

[10] Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood, 112(13), 4808–4817. https://doi.org/10.1182/blood-2008-07-077958

[11] Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood, 112(13), 4808–4817. https://doi.org/10.1182/blood-2008-07-077958

[12] Aguayo, A., Kantarjian, H. M., Estey, E. H., Giles, F. J., Verstovsek, S., Manshouri, T., Gidel, C., O’Brien, S., Keating, M. J., & Albitar, M. (2002). Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer, 95(9), 1923– 1930. https://doi.org/10.1002/cncr.10900

[13] Kantarjian, H. M., Talpaz, M., O’Brien, S., Giles, F., Garcia-Manero, G., Faderl, S., Thomas, D., Shan, J., Rios, M. B., & Cortes, J. (2003). Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood, 101(2), 473–475. https://doi.org/10.1182/blood-2002- 05-1451

[14] Butt, R., Khattak, N. N., Ziaudin, N., Nangyal, H., & Nangyal, H. (2015). Chronic myeloid leukemia: The mutational landscape. International Journal of Microbiology and Allied Sciences. IJOMAS.

[15] Chereda, B., & Melo, J. V. (2015). Natural course and biology of CML. Annals of Hematology, 94(Suppl 2), S107–S121. https://doi.org/10.1007/s00277-015-2325-z

[16] Khorashad, J. S., Anand, M., Marin, D., Saunders, S., Al-Jabary, T., Iqbal, A., Margerison, S., Melo, J. V., Goldman, J. M., Apperley, J. F., & Kaeda, J. (2006). The presence of a BCR–ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia, 20(4), 658–663. https://doi.org/10.1038/sj.leu.2404137

[17] Marin, D., Kaeda, J., Szydlo, R., Saunders, S., Fleming, A., Howard, J., Andreasson, C., Bua, M., Olavarria, E., Rahemtulla, A., Dazzi, F., Kanfer, E., Goldman, J. M., & Apperley, J. F. (2005). Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: Patterns of residual leukemia and prognostic factors for cytogenetic relapse. Leukemia, 19(4), 507–512. https://doi.org/10.1038/sj.leu.2403664

[18] Ottmann, O. G., Druker, B. J., Sawyers, C. L., Goldman, J. M., Reiffers, J., Silver, R. T., Tura, S., Fischer, T., Deininger, M. W., Schiffer, C. A., Baccarani, M., Gratwohl, A., Hochhaus, A., Hoelzer, D., Fernandes-Reese, S., Gathmann, I., Capdeville, R., & O’Brien, S. G. (2002). A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood, 100(6), 1965–1971. https://doi.org/10.1182/blood-2001-12-0181

[19] Druker, B. J. (2002). Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML. Oncogene, 21(56), 8541–8546. https://doi.org/10.1038/sj.onc.1206081

[20] Rocca, S., Carrà, G., Poggio, P., Morotti, A., & Brancaccio, M. (2018). Targeting few to help hundreds: JAK, MAPK and ROCK pathways as druggable targets in atypical chronic myeloid leukemia. Molecular Cancer, 17, 40. https://doi.org/10.1186/s12943- 018-0774-4

[21] Steelman, L. S., Pohnert, S. C., Shelton, J. G., Franklin, R. A., Bertrand, F. E., & McCubrey, J. A. (2004). JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCRABL in cell cycle progression and leukemogenesis. Leukemia, 18(2), 189–218. https://doi.org/10.1038/sj.leu.2403241 [22] Zaharieva, M., Amudov, G., Konstantinov, S., & Guenova, M. (2013). In M. Guenova & G. Balatzenko (Eds.), Modern therapy of chronic myeloid leukemia (p. 227).

[23] Morozova E, Vlasova Y, Pryanishnikova M, Lepik K, Afanasyev B. Efficacy of dasatinib in a CML patient in blast crisis with F317L mutation: A case report and literature review. Biomarker Insights. 2015;10:BMI. S22438.

[24] An, X., Tiwari, A. K., Sun, Y., Ding, P.-R., Ashby, C. R., Jr., & Chen, Z.-S. (2010). BCR–ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review. Leukemia Research, 34(10), 1255–1268. https://doi.org/10.1016/j.leukres.2010.04.016

[25] Jabbour, E., Kantarjian, H., & Cortes, J. (2015). Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: An evolving treatment paradigm. Clinical Lymphoma, Myeloma & Leukemia, 15(6), 323–334. https://doi.org/10.1016/j.clml.2015.03.006

[26] Patel, A. B., Solomon, A. R., Mauro, M. J., & Ehst, B. D. (2016). Unique cutaneous reaction to second-and third-generation tyrosine kinase inhibitors for chronic myeloid leukemia. Dermatology (Basel, Switzerland), 232(1), 122–125. https://doi.org/10.1159/000437383

[27] Inches, G., & Crestani, F. (Eds.). (2012). Overview of the International Sexual Predator Identification Competition at PAN-2012. CLEF (Online working notes/labs/workshop). Citeseer.

[28] Moore, A. S., Blagg, J., Linardopoulos, S., & Pearson, A. D. (2010). Aurora kinase inhibitors: Novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia, 24(4), 671–678. https://doi.org/10.1038/leu.2010.15

[29] Okabe, S., Tauchi, T., Tanaka, Y., & Ohyashiki, K. (2018). Therapeutic targeting of Aurora A kinase in Philadelphia chromosome-positive ABL tyrosine kinase inhibitor-resistant cells. Oncotarget, 9(65), 32496–32506. https://doi.org/10.18632/oncotarget.25985

[30] Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3(7), 730–737. https://doi.org/10.1038/nm0797-730

[31] Holyoake, T., Jiang, X., Eaves, C., & Eaves, A. (1999). Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood, 94(6), 2056–2064. https://doi.org/10.1182/blood.V94.6.2056

[32] Copland, M., Jørgensen, H. G., & Holyoake, T. L. (2005). Evolving molecular therapy for chronic myeloid leukaemia—Are we on target? Hematology (Amsterdam, Netherlands), 10(5), 349–359. https://doi.org/10.1080/10245330500234195

[33] Jones, C., Hughes, J., Bellouin, N., Hardiman, S., Jones, G., Knight, J., Liddicoat, S., O’Connor, F. M., Andres, R. J., Bell, C., Boo, K.-O., Bozzo, A., Butchart, N., Cadule, P., Corbin, K. D., Doutriaux-Boucher, M., Friedlingstein, P., Gornall, J., Gray, L., . . . Zerroukat, M. (2011). The HadGEM2-ES implementation of CMIP5 centennial simulations. Geoscientific Model Development, 4(3), 543–570. https://doi.org/10.5194/gmd-4-543-2011

[34] Misaghian, N., Ligresti, G., Steelman, L. S., Bertrand, F. E., Bäsecke, J., Libra, M., Nicoletti, F., Stivala, F., Milella, M., Tafuri, A., Cervello, M., Martelli, A. M., & McCubrey, J. A. (2009). Targeting the leukemic stem cell: The holy grail of leukemia therapy. Leukemia, 23(1), 25–42. https://doi.org/10.1038/leu.2008.246

[35] Ramírez, F., Bhardwaj, V., Arrigoni, L., Lam, K. C., Grüning, B. A., Villaveces, J., Habermann, B., Akhtar, A., & Manke, T. (2018). High-resolution TADs reveal DNA sequences underlying genome organization in flies. Nature Communications, 9(1), 189. https://doi.org/10.1038/s41467-017-02525-w