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Molecular pathogenesis of chronic myeloid leukemia

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Summary

Chronic myeloid leukemia (CML) is a paradigm for effective targeted therapy and is characterized by the hallmark BCR-ABL1 fusion. Although survival of affected patients has dramatically increased with the introduction of tyrosine kinase inhibitor therapy, kinase-dependent and -independent resistance mechanisms remain a problem and therefore new clinical strategies based on our growing knowledge of cellular processes are required. New diagnostic opportunities support this task and will change disease management in the future.

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References

  1. Mughal TI, Radich JP, Deininger MW, Apperley JF, Hughes TP, Harrison CJ, et al. Chronic myeloid leukemia: reminiscences and dreams. Haematologica. 2016;101:541–58.

    Article  CAS  Google Scholar 

  2. Hernández SE, Krishnaswami M, Miller AL, Koleske AJ. How do Abl family kinases regulate cell shape and movement? Trends Cell Biol. 2004;14:36–44.

    Article  Google Scholar 

  3. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009;113:1619–30.

    Article  Google Scholar 

  4. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172–83.

    Article  CAS  Google Scholar 

  5. Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS. Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Biol. 2002;9:117–20.

    CAS  PubMed  Google Scholar 

  6. Zhang X, Subrahmanyam R, Wong R, Gross AW, Ren R. The NH(2)-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol Cell Biol. 2001;21:840–53.

    Article  CAS  Google Scholar 

  7. Mughal T, Cortes J, Cross NCP, Donato N, Hantschel O, Jabbour E, et al. Chronic myeloid leukemia – some topical issues. Leukemia. 2007;21:1347–52.

    Article  CAS  Google Scholar 

  8. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251–3.

    Article  CAS  Google Scholar 

  9. Lichty BD, Keating A, Callum J, Yee K, Croxford R, Corpus G, et al. Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukaemia. Br J Haematol. 1998;103:711–5.

    Article  CAS  Google Scholar 

  10. van Rhee F, Hochhaus A, Lin F, Melo JV, Goldman JM, Cross NC. p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias. Blood. 1996;87:5213–7.

    PubMed  Google Scholar 

  11. Jinawath N, Norris-Kirby A, Smith BD, Gocke CD, Batista DA, Griffin CA, et al. A rare e14a3 (b3a3) BCR-ABL fusion transcript in chronic myeloid leukemia: diagnostic challenges in clinical laboratory practice. J Mol Diagn. 2009;11:359–63.

    Article  CAS  Google Scholar 

  12. Hantschel O, Superti-Furga G. Regulation of the c‑Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33–44.

    Article  CAS  Google Scholar 

  13. Rumpold H, Webersinke G. Molecular pathogenesis of Philadelphia-positive chronic myeloid leukemia – is it all BCR-ABL? Curr Cancer Drug Targets. 2011;11:3–19.

    Article  CAS  Google Scholar 

  14. Warsch W, Walz C, Sexl V. JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. Blood. 2013;122:2167–75.

    Article  CAS  Google Scholar 

  15. Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001;20:6188–95.

    Article  CAS  Google Scholar 

  16. Samanta A, Perazzona B, Chakraborty S, Sun X, Modi H, Bhatia R, et al. Janus kinase 2 regulates Bcr–Abl signaling in chronic myeloid leukemia. Leukemia. 2010;25:463–72.

    Article  Google Scholar 

  17. Sawyers CL. The role of myc in transformation by BCR-ABL. Leuk Lymphoma. 1993;11(Suppl 1):45–6.

    Article  Google Scholar 

  18. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18:189–218.

    Article  CAS  Google Scholar 

  19. Ozaki K‑I, Kosugi M, Baba N, Fujio K, Sakamoto T, Kimura S, et al. Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib. Biochem Biophys Res Commun. 2010;391:1610–5.

    Article  CAS  Google Scholar 

  20. Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res. 2012;18:930–7.

    Article  CAS  Google Scholar 

  21. Zeng X, Zhao H, Li Y, Fan J, Sun Y, Wang S, et al. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia. Autophagy. 2015;11:355–72.

    Article  Google Scholar 

  22. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, et al. BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet. 2002;30:48–58.

    Article  CAS  Google Scholar 

  23. Eiring AM, Harb JG, Neviani P, Garton C, Oaks JJ, Spizzo R, et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell. 2010;140:652–65.

    Article  CAS  Google Scholar 

  24. Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim D‑W, Nicolini FE, et al. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood. 2016;127:703–12.

    Article  CAS  Google Scholar 

  25. Soverini S, De Benedittis C, Machova Polakova KM, Linhartova J, Castagnetti F, Gugliotta G, et al. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients. Oncotarget. 2016;7(16):21982–90.

    Article  Google Scholar 

  26. Parker WT, Ho M, Scott HS, Hughes TP, Branford S. Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile. Blood. 2012;119:2234–8.

    Article  CAS  Google Scholar 

  27. O’Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513–26.

    Article  Google Scholar 

  28. Cross NCP, White HE, Ernst T, Welden L, Dietz C, Saglio G, et al. Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale. Leukemia. 2016;30(9):1844–52.

    Article  CAS  Google Scholar 

  29. Soverini S, De Benedittis C, Mancini M, Martinelli G. Present and future of molecular monitoring in chronic myeloid leukaemia. Br J Haematol. 2016;173:337–49.

    Article  Google Scholar 

  30. Alikian M, Ellery P, Forbes M, Gerrard G, Kasperaviciute D, Sosinsky A, et al. Next-Generation Sequencing-Assisted DNA-Based Digital PCR for a Personalized Approach to the Detection and Quantification of Residual Disease in Chronic Myeloid Leukemia Patients. J Mol Diagn. 2016;18:176–89.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Labor für Molekularbiologie und Tumorzytogenetik, Abteilung Interne I, Krankenhaus der Barmherzigen Schwestern Linz BetriebsgesmbH, Seilerstätte 4, 4010, Linz, Austria

    Gerald Webersinke

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  1. Gerald Webersinke
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Correspondence to Gerald Webersinke.

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G. Webersinke declares that he has no competing interests.

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Webersinke, G. Molecular pathogenesis of chronic myeloid leukemia. memo 9, 163–167 (2016). https://doi.org/10.1007/s12254-016-0294-0

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  • DOI: https://doi.org/10.1007/s12254-016-0294-0

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