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Editorials
13. Cui S, Kolodziej KE, Obara N, et al. Nuclear receptors TR2 and TR4rcruit multiple epigenetic transcriptional corepressors that asso- ciate specifically with the embryonic β-type globin promoters in dif- ferentiated adult erythroid cells. Mol Cell Biol. 2011;31(16):3298- 3311.
14. Xu J, Bauer DE, Kerenyi MA, et al. Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci U S A. 2013;110(16):6518-6523.
15. Du Q, Luu P-L, Stirzaker C, Clark SJ. Methyl-CpG-binding domain proteins:readers of the epigenome. Epigenomics. 2015;7(6):1051- 1073.
16. Menafra R, Stunnenberg HG. MBD2 and MBD3: elusive functions and mechanisms. Front Genet. 2014;5:428.
17. Rupon JW, Wang SZ, Gaensler K, Lloyd J, Ginder GD. Methyl bind- ing domain protein 2 mediates gamma-globin gene silencing in adult human betaYAC transgenic mice. Proc Natl Acad Sci U S A. 2006;103(17):6617-6622.
18. Kransdorf EP, Wang SZ, Zhu SZ, Langston TB, Rupon JW, Ginder GD. MBD2 is a critical component of a methyl cytosine-binding pro- tein complex isolated from primary erythroid cells. Blood. 2006;108(8):2836-2845.
19. Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 2001;15(6):710-723.
20. Sher F, Hossain M, Seruggia D, et al. Rational targeting of a NuRD subcomplex guided by comprehensive in situ mutagenesis. Nat Genet. 2019;51(7):1149-1159.
Are we ready to use precision medicine in chronic myeloid leukemia practice?
Dennis Dong Hwan Kim
Leukemia Program, Department of Medical Oncology and Hematology, Princess Margraret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
adult erythroid cells. Transl Res. 2015;165(1):115-125.
4. Suzuki M, Yamamoto M, Engel JD. Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies.
Mol Cell Biol. 2014;34(19):3560-3569.
5. Lavelle D, Engel JD, Saunthararajah Y. Fetal hemoglobin induction
by epigenetic drugs. Semin Hematol. 2018;55(2):60-67.
6. Yu X, Azzo A, Bilinovich SM, et al. Disruption of the MBD2-NuRD complex but not MBD3-NuRD induces high level HbF expression in
human erythroid cells. Haematologica 2019;104(12):2361-2371.
7. Le Guezennec X, Vermeulin M, Brinkman AB, et al. MBD2/NURD and MBD3/NURD, two distinct complexes with different biochem-
ical and functional properties Mol Cell Biol. 2006;26(3):843-851.
8. Van der Ploeg LH, Flavell RA. DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tis-
sues. Cell. 1980;19(4):947-958.
9. DeSimone J, Heller P, Hall L, Zwiers D. 5-azacytidine stimulates fetal
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10. Ginder GD, Whitters MJ, Pohlman JK. Activation of a chicken
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11. Vinjamur DS, Bauer DE, Orkin SH. Recent progress in understanding and manipulating haemoglobin witching for the haemoglo-
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Wake-up sleepy gene: Reactivating fetal globin for β-hemoglo- binopathies. Trends Genet. 2018;34(12):927-940.
E-mail: DENNIS DONG HWAN KIM - dr.dennis.kim@uhn.ca doi:10.3324/haematol.2019.231753
Over the last two decades, the introduction of tyro- sine kinase inhibitors (TKI) and advances in BCR- ABL1 monitoring using quantitative polymerase chain reaction (qPCR) have significantly improved treat- ment outcomes in chronic myeloid leukemia (CML) patients.1 Not only the introduction of TKI increased the life expectancy of CML patients (98% of age-matched healthy control), but also the incorporation of BCR-ABL1 monitoring using qPCR significantly improved outcomes of CML patients by identifying those cases developing TKI failure and progressing to the advanced phase.2,3 However, it is still challenging to predict patients at high risk for TKI failure at initial diagnosis of CML before commencing TKI therapy. Thus, major challenges still remain, including lack of accurate risk stratification at initial diagnosis.
The current algorithm for CML management is mainly based on monitoring BCR-ABL1 using qPCR.3 Despite its good performance, there are still remaining issues some of which include: i) how to select upfront TKI drug in a newly diagnosed CML patient (imatinib vs. newer generation TKI); ii) how to switch TKI therapy in a patient who devel- oped TKI resistance, but without ABL1 kinase domain mutations; and iii) how to predict which patients are at high risk of progression to blastic crisis. Thus, there is an urgent demand for novel biomarkers in managing CML beyond monitoring BCR-ABL1 fusion transcripts. Given this, how can we go forward from here?
Let us look back at routine CML practice 20 years ago
when TKI therapy and qPCR-based BCR-ABL1 monitoring 4
were not available. When a patient was newly diagnosed with chronic phase CML, the first step would be the iden- tification of an HLA-matched donor for allogeneic hematopoietic cell transplantation (HCT) and co-ordination of allogeneic HCT within two years from initial diagnosis before the patient progressed to advanced phase. If an appropriate donor was not available, interferon therapy was a treatment of choice. Disease monitoring was mainly based on the metaphase cytogenetic test for which bone marrow aspiration should be performed every 6 months to assess cytogenetic response. Let us compare it with current CML practice, which has changed significantly over the last two decades. First, we no longer initiate a search for an HLA-matched donor search until TKI failure or intolerance to more than two TKI is suspected.3 Bone marrow exami- nation does not need to be repeated as frequent as BCR- ABL1 qPCR on peripheral blood which is the mainstay of disease monitoring. So, what will happen in the future? CML practice will evolve and will be transformed again from the current routine practice. However, what we do not know yet is how this will be achieved and what changes will be applied.
Precision medicine is becoming the mainstream of future medicine. It has been implemented in the clinical practice in acute myeloid leukemia (AML),5 and myeloproliferative
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