Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia

Urayama, Kevin Y.; Chokkalingam, Anand P.; Manabe, Atsushi; Mizutani, Shuki

doi:10.1007/s12185-012-1220-9

Cited by 19 publications

(16 citation statements)

References 106 publications

(159 reference statements)

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“…Acute lymhoblastic leukemias (ALLs) are neoplasms of lymphoid precursors and are common among childhood malignancies [55]. With the advent of high-resolution genome-wide profiling approaches, a variety of genetic alterations, deletions and mutations have been newly identified on the ALL genomes that cooperate with previously characterized chromosomal alterations [56-58].…”

Section: A New High-risk Model Of B-all Supported By Ikaros Mutationsmentioning

confidence: 99%

Ikaros fingers on lymphocyte differentiation

Yoshida

Georgopoulos

2014

Int J Hematol

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The Ikaros family of DNA binding proteins are critical regulators of lymphocyte differentiation. In multipotent hematopoietic progenitors, Ikaros supports transcriptional priming of genes promoting lymphocyte differentiation. Ikaros targets the Nucleosome Remodeling Deacetylase complex (NuRD) to lymphoid lineage genes, thereby increasing chromatin accessibility and transcriptional priming. After lymphoid lineage specification, Ikaros expression is raised to levels characteristic of intermediate B cell and T cell precursors, which is necessary to support maturation and prevent leukemogenesis. Loss of Ikaros in T cell precursors allows the NuRD complex to repress lymphocyte genes and extends its targeting to genes that support growth and proliferation, causing their activation and triggering a cascade of events that leads to leukemogenesis. Loss of Ikaros in B cell precursors blocks differentiation and perpetuates stromal adhesion by enhancing integrin signaling. The combination of integrin and cytokine signaling in Ikaros-deficient pre-B cells promotes their survival and self-renewal. The stages of lymphocyte differentiation that are highly dependent on Ikaros are underscored by changes in Ikaros transcription, supported by a complex network of stage-specific regulatory networks that converge upon the Ikzf1 locus. It is increasingly apparent that understanding the regulatory networks that operate upstream and downstream of Ikaros is critical not only for our understanding of normal lymphopoiesis, but also in placing the right finger on the mechanisms that support hematopoietic malignancies in mouse and human.

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Section: A New High-risk Model Of B-all Supported By Ikaros Mutationsmentioning

confidence: 99%

Ikaros fingers on lymphocyte differentiation

Yoshida

Georgopoulos

2014

Int J Hematol

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“…As reviewed previously [55], the two approaches should be viewed as complementary strategies for identification of disease associated loci as they both have their respective strengths and weaknesses depending on the study being conducted. A review of the literature identified six xMHC childhood ALL candidate gene studies of non-classical HLA loci, and statistically significant associations have been reported for SNPs of the HFE , HSPA1B and BAT3 genes [56,57,58].…”

Section: Discussionmentioning

confidence: 99%

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

et al. 2013

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The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.

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“…Using technological approaches available at the time, study investigators most often looked at SNPs within single genes that were thought to be involved in the process of leukemia development and progression. When reviewing the hundreds of published studies available, the majority of these candidate genes associated with the biology of ALL can be divided into the following 5 main categories: (1) folate metabolism/transport, (2) xenobiotic metabolism/transport, (3) immune function, (4) DNA repair, and (5) cell cycle 9 10. Many of these studies have mixed and even conflicting results, demonstrating the difficulty in identifying risk genes for cancer.…”

Section: Candidate Gene Approachesmentioning

confidence: 99%

Applying molecular epidemiology in pediatric leukemia

Schiffman

2016

J Investig Med

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Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members.

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Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia

Cited by 19 publications

References 106 publications

Ikaros fingers on lymphocyte differentiation

Ikaros fingers on lymphocyte differentiation

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

Applying molecular epidemiology in pediatric leukemia

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