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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (1) : 1-9     DOI: 10.1007/s11684-015-0381-3
REVIEW |
Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia
Ching-Hon Pui()
Departments of Oncology and Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; the University of Tennessee Health Science Center, Memphis, TN 38105, USA
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Abstract  

With the cure rate of childhood acute lymphoblastic leukemia (ALL) approaching 90%, further improvement in the treatment outcome and quality of life of patients will require better understanding of the mechanisms of drug resistance, identifying new leukemic cell genetic lesions that are amendable to available target therapy, and optimizing treatment based on host pharmacodynamics and pharmacogenomics. Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications. In this regard, several novel fusion transcripts are responsive to ABL tyrosine kinase inhibitors and potentially to JAK inhibitors. Genome-wide analyses have also unraveled the role of inherited cancer predisposing genes and small nucleotide polymorphisms of several genes in the development of childhood ALL. These advances promise to lead to more sophisticated personalized treatment strategies in the near future.

Keywords pharmacogenomics      acute lymphoblastic leukemia      genomics      pharmacogenetics     
Corresponding Authors: Ching-Hon Pui   
Online First Date: 12 December 2014    Issue Date: 02 March 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0381-3     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I1/1
White/Non-black (%) Black (%)
Hyperdiploidy>50 28.2 11.4
ETV6-RUNX1 18.6 21.5
BCR-ABL1-like 8.8 3.8
TCF3-PBX1 4.1 13.9
ERG 3.1 1.3
Hypodiploidy 2.6 -
BCR-ABL1 1.7 3.8
Rearranged MLL 1.4 3.8
CRLF2 (not BCR-ABL1-like) 1.7 1.3
Other B 16.0 20.3
T-cell 12.6 12.7
Early T-cell precursor 1.2 6.3
Tab.1  Estimated frequency of specific subtypes of ALL by race in patients treated at St. Jude Children’s Research Hospital between 2000 and 2007
Study group Ethnic study population Sample size (n) Susceptibility loci Comment References
COG, SJCRH Caucasian 441 ARID5BIKZF1 ARID5B associated with hyperdiploid ALL Trevi?o et al. [23]
UKCCS, MRS Caucasian 907 ARID5BIKZF1CEBPE ARID5B associated with hyperdiploid ALL Papaemmanuil et al. [24]
UK, BFM, Spain, Hungary, Canada Caucasian 3293 ARID5BIKZF1CEBPECDKN2A CDKN2A associated with both B- and T-ALL Sherborne et al. [25]
COG, SJCRH Caucasian, Black, Hispanic 2450 ARID5BIKZF1CEBPECDKN2ABMI1-PIP4K2A The number of risk alleles associated positively with the risk of ALL Xu et al. [26]
AIEOP, BFM, COALL Caucasian 1370 TP63PTPRJ TP63 and PTPRJ associated with ETV6-RUNX1-rearranged ALL. Ellinghaus et al. [28]
COG, SJCRH Caucasian, Black, Hispanic 682 GATA3 GATA3 associated with Philadelphia chromosome-like ALL and poor prognosis Perez-Andreu et al. [29]
UKCCS, MRC UKALL, BFM Caucasian 3107 ARID5BIKZF1CEBPECDKN2ABMI1-PIP4K2AGATA3 GATA3 associated with increased risk of ALL risk and poor prognosis Migliorini et al. [30]
Tab.2  Genome-wide association of studies of susceptibility of childhood acute lymphoblastic leukemia
Drug Genes Comments References
Asparaginase HLA-DRB1*07:01 HLA-DRB1*07:01-encoded protein is associated with higher incidence of the development of anti-asparaginase antibody and a higher frequency of asparaginase hypersensitivity, probably through its high-affinity binding to asparaginase epitopes. Christian et al. [37]
Methotrexate SLCO1B1 Methotrexate clearance is associated with polymorphisms of SLCO1B1 which encode a hepatic solute carrier organic anion transporter that mediates disposition of many medications including methotrexate. Ramsey et al. [38,39]
Mercaptopurine TPMT, PACSIN2 Genetic polymorphisms in TPMT (thiopurine S-methyltransferase) are known to have a marked effect on mercaptopurine metabolism and toxicity. By modulating TPMT activity, polymorphism in PACSIN2 (protein kinase C and casein kinase substrate in neurons protein 2) increases the severity of gastrointestinal toxicity associated with mercaptopurine therapy. Stocco et al. [40]
Corticosteroids CRHR1 Polymorphisms of CRHR1 that encodes corticotropin-releasing hormone receptor-1 are associated with low bone density in male patients treated with corticosteroids, probably due to its effect on the release of corticotropin from the anterior pituitary, altering levels of circulating endogenous glucocorticoids. Jones et al. [41]
Corticosteroids PAI-1 A polymorphism of PAI-1 that encodes plasminogen activator inhibitor-1 is associated with increased risk of dexamethasone-related osteonecrosis. It was speculated that high levels of PAI-1, by inhibiting fibrinolysis and resulting increased intraosseous venous pressure blocking blood flow to the bone, cause osteonecrosis. French et al. [42]
Anthracycline HAS3 A variant of hyaluronan synthase 3 gene is associated with increased risk of anthracycline-related cardiomyopathy, which could be due to inadequate remodeling or inadequate protection of the heart from reactive oxygen species after anthracycline treatment. Wang et al. [43]
Vincristine CEP72 A polymorphism of CEP72 reduces expression of its encoded centrosomal protein 72kDa that functions as the major microtubule-organizing center and regulates proper bipolar spindle formation and is associated with an increased risk of vincristine-induced neuropathy. Diouf et al. [44]
Tab.3  Selected examples of genomic determinants of drug toxicities
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