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82 Part I Molecular and Cellular Basis of Hematology

analysis of genetic variations in drug-metabolizing enzymes and how alter the function of enzymes they encode, as well as CNVs or
those variations translate into inherited differences in drug effects. epigenetic signatures that alter the expression of functionally rel-
Subsequently, the field has incorporated genome-wide approaches evant genes, can influence either drug activation or inactivation, and
to identify networks of genes that govern the clinical response to ultimately determine the extent of drug effects. This is most evident
drug therapy (i.e., pharmacogenomics). The terms pharmacogenet- when polymorphic genes encode enzymes that are involved in crucial
ics and pharmacogenomics, however, are generally considered to be pathways of elimination or activation of the administered medica-
synonymous for all practical purposes. With the recognition that tion. It should also be recognized that genetic polymorphism in
epigenetic modification affects gene expression and can contribute genes that encode the protein targets of medications (e.g., VKORC1,
to variability in drug effects, the field of pharmacoepigenomics has the target of warfarin) can also have a significant influence on
gained additional attention and importance. drug effects.
Overall, pharmacogenomics can be viewed as a broad strategy The focus of this chapter is to provide examples that are rel-
to establish models of drug disposition and effects by integrating evant to hematologists to illustrate the potential impact of genome
information from genome sequencing, functional genomics, high- variation on the effects of medications. We discuss enzymes involved
throughput molecular analyses, pharmacokinetics (e.g., drug metabo- in inactivation of the antileukemic agent MP, as well as genes
lism and disposition), and pharmacodynamics (treatment response). encoding the enzyme (CYP2C9) that metabolizes active warfarin
Approaches to establish pharmacogenomic models include candidate and the gene that encodes its target (VKORC1). These examples
gene analyses (which focus on the analysis of single genes or sets of therefore involve both phase I (CYP2C9) and phase II (thiopurine
functionally related genes in pathways thought to be important for S-methyltransferase [TPMT]) drug-metabolizing enzymes and the
the medicine under study) and more agnostic genome-wide analyses. target of the most widely prescribed anticoagulant. Our examples
Pharmacogenomic models can be used to maximize efficacy and include both inherited genome variations (CYP2C9, TPMT,
reduce toxicity of existing medications, as well as to identify novel NUDT15, and VKORC1) and somatically acquired genome variants
therapeutic targets. (NT5C2) that have been shown to alter drug effects in humans.
Comprehensive reviews on pharmacogenomics and epigenomics This is a rapidly evolving component of “precision medicine,” thus
are available elsewhere. 1–3,6,7 Herein, clinically relevant examples are providing an understanding of their relevance and potential is of
provided to illustrate the potential of pharmacogenomics and epig- greater value than attempting a current and comprehensive literature
enomics to improve current drug therapy for hematologic disorders, review.
to prevent hematologic toxicity, and perhaps to identify novel targets
for developing new therapeutic approaches in hematology.
Thiopurines and Inherited Variants in TPMT and
NUDT15, and Acquired Somatic Variants in NT5C2
OPTIMIZATION OF DRUG THERAPY
MP is metabolized by numerous enzymes, either to activate it to
Drug effects are typically determined by the interplay of several thioguanine nucleotides (TGNs) or to inactivate it via methylation or
gene products that influence the pharmacokinetics and pharmaco- dephosphorylation of TGNs. Although there is genetic polymorphism
dynamics of medications. Pharmacokinetics entails characterization in enzymes involved in MP activation (e.g., hypoxanthine phospho-
of the absorption, distribution, metabolism, and excretion (ADME) ribosyltransferase 1 [HPRT1]), there is little evidence that genetic
of medications. Pharmacodynamics is the relationship between the polymorphisms in these enzymes play an important role in controlling
pharmacokinetic properties of drugs and their pharmacologic effects, the pharmacologic effects of MP, with the exception of patients who
either desired or adverse. The ultimate goals of pharmacogenom- inherit HPRT1 deficiency, an X-linked disease that occurs in approxi-
ics and pharmacoepigenomics in this context are to elucidate the mately 1 in 350,000 Caucasian males (Lesch–Nyhan syndrome). In
inherited determinants for drug disposition and response to select contrast, genetic polymorphisms in two enzymes involved in the
medications and dosages on the basis of each patient’s inherited inactivation of thiopurines (MP, and the MP prodrug azathioprine
ability to metabolize, eliminate, and respond to specific drugs. A and thioguanine) increase the accumulation of their active TGNs,
model of how polygenic variables can determine drug response is thereby increasing the risk of hematopoietic toxicity; TPMT and
illustrated in Fig. 8.1. NUDT15 (nucleoside diphosphate linked moiety X-type motif 15).
Inherited variants in TPMT were first discovered in the 1990s, with
GENETIC VARIATIONS THAT INFLUENCE two major inactive variant alleles accounting for the majority of inher-
ited TPMT deficiency in major world populations studied to date
DRUG DISPOSITION (TPMT*3C [rs1800460] for persons of Asian and African ancestry,
and TPMT*3A [rs1142345 and rs1800469] for persons of European
Drug Metabolism ancestry). TPMT*3A, TPMT*3C, and TPMT*2 (rs1800462) account
for more than 95% of the clinically relevant TPMT variants; variant
There are many enzymes involved in drug metabolism, which are TPMT alleles encode unstable proteins. Patients who are heterozygous
often categorized into phase I reactions that involve oxidation, (5% to 10% of persons) are about five times more likely to develop
reduction, or hydrolysis of medications, and phase II enzymes that hematologic toxicity, whereas patients who inherit two variant alleles
conjugate drugs via acetylation, glucuronidation, sulfation, or meth- (1 in 300 persons) will all develop hematologic toxicity if treated with
ylation. Although phase I metabolism often inactivates medications, conventional doses of thiopurines. 10
this is not always the case, as exemplified by codeine’s activation It has been recognized for many years that patients of Asian ances-
by cytochrome P450 CYP2D6 and clopidogrel’s activation via try develop more hematologic toxicity than patients of European or
CYP2C19. Phase II conjugation generally makes medications more African ancestry, yet the frequency of nonfunctional TPMT alleles
water soluble and therefore more readily excreted in the urine, but is lower in Asians. Important new insights were recently provided
some phase II conjugates have pharmacologic effects. Although the by the identification of variant alleles of NUDT15 in South Korean
liver is generally considered the major organ for drug metabolism, patients with inflammatory bowel disease who developed hematologic
11
phase I and phase II metabolic enzymes are found in many other toxicity while receiving azathioprine therapy. The NUDT15 variant
tissues, including the kidney, intestinal tract, lung, brain, spleen, was very strongly related to thiopurine hematopoietic toxicity. In a
erythrocytes, and lymphocytes. GWAS of children with ALL receiving MP therapy, both TPMT and
Essentially all genes encoding drug-metabolizing enzymes with NUDT15 were significantly related to thiopurine intolerance in U.S.
12
more than 30 families of enzymes in humans exhibit genetic varia- children. Together, these studies show that genetic polymorphisms
tion, many of which translate into functional changes in the proteins in both of these genes influence thiopurine tolerance, and that TPMT
encoded. Inheritance of genes containing sequence variations that variants are more common in patients of European and African