Related Experiment Video

Updated: Jun 23, 2026

Modeling Chemotherapy Resistant Leukemia In Vitro
08:41

Modeling Chemotherapy Resistant Leukemia In Vitro

Published on: February 9, 2016

Genetic Determinants of Treatment-Related Bone Toxicity in Pediatric Acute Lymphoblastic Leukemia

Rachid Abaji1,2, Vincent Gagné1, Émilie Espagne1

  • 1Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Québec, Canada.

Clinical Pharmacology and Therapeutics
|June 22, 2026
PubMed

Insights

Genetic variants in PGAP2, BCL2L11, and ACP1-SH3YL1 influence bone toxicity in children with acute lymphoblastic leukemia (ALL). These genetic factors remain relevant in modern treatments, impacting osteonecrosis and fractures.

Area of Science:

  • Genetics
  • Pharmacogenomics
  • Pediatric Oncology

Background:

  • Corticosteroid-induced bone toxicities, including osteonecrosis and fractures, are significant complications in children treated for acute lymphoblastic leukemia (ALL).
  • The genetic underpinnings of these adverse bone effects are not fully understood, necessitating further investigation into genetic risk factors.

Purpose of the Study:

  • To identify novel genetic contributors to bone toxicity in pediatric ALL patients.
  • To evaluate the clinical relevance of newly identified and previously known genetic risk variants in contemporary treatment protocols.
  • To explore the functional role of identified genetic variants in the development of bone toxicity.

Main Methods:

  • Whole-exome sequencing was employed in a discovery cohort to identify genetic variants associated with osteonecrosis.
  • A novel association with a PGAP2 gene variant was identified and validated in an independent replication cohort.
  • Previously reported candidate gene variants and the novel PGAP2 variant were assessed in a recent cohort, alongside transcriptomic analyses.

Main Results:

  • A novel PGAP2 gene variant was significantly associated with osteonecrosis and the combined osteonecrosis-fracture phenotype.
  • Variants in BCL2L11 and the ACP1-SH3YL1 locus were linked to bone fractures, with synergistic effects modulated by treatment factors like corticosteroid exposure.
  • Transcriptomic data indicated isoform-specific expression shifts in PGAP2 in patients experiencing osteotoxicity, suggesting a role in altered gene regulation or splicing.

Conclusions:

  • PGAP2, BCL2L11, and ACP1-SH3YL1 variants are clinically relevant predictors of bone toxicity in pediatric ALL patients undergoing evolving treatment protocols.
  • The manifestation of these genetic risks is context-dependent, influenced by pharmacologic exposures and specific treatment strategies.
  • Further research into the molecular mechanisms underlying these pharmacogenomic associations is warranted to mitigate bone toxicity risks.

More Related Videos

Murine Model of Leukemia Relapse to Induction Chemotherapy for Acute Lymphoblastic Leukemia08:31

Murine Model of Leukemia Relapse to Induction Chemotherapy for Acute Lymphoblastic Leukemia

Published on: October 17, 2025

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

Related Concept Videos

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Bone Marrow Sampling and Transplants01:22

Bone Marrow Sampling and Transplants

Bone marrow transplant is a potential cure for several diseases, including cancer and specific genetic disorders. Notably, this procedure is applicable for patients suffering from aplastic anemia, certain types of leukemia, severe combined immunodeficiency disease (SCID), Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, thalassemia, sickle-cell disease, and certain cancers.
The transplant begins with high doses of chemotherapy and radiation treatment, which aim to destroy the...
Pharmacokinetics in Pediatric Patients: Drug Excretion01:26

Pharmacokinetics in Pediatric Patients: Drug Excretion

In pediatric medicine, understanding the renal function and drug elimination nuances is crucial for administering safe and effective treatments. Newborns, in particular, display markedly slower renal functions than adults, profoundly affecting how drugs are cleared from their bodies. This slower drug clearance requires clinicians to extend the dosing intervals for many medications to prevent drug accumulation and toxicity while ensuring therapeutic efficacy.One key area where these adjustments...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase01:27

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...