We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10<sup>-8</sup>), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10<sup>-8</sup>) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10<sup>-8</sup>), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10<sup>-8</sup>).
We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10<sup>-8</sup>), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10<sup>-8</sup>) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10<sup>-8</sup>), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10<sup>-8</sup>).
These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL.
Toward this goal, we sequenced the exomes of a childhood ALL family consisting of mother, father and two non-twinned siblings diagnosed with concordant pre-B hyperdiploid ALL and previously shown to have inherited a rare form of PRDM9, a histone H3 methyltransferase involved in crossing-over at recombination hotspots and Holliday junctions.
These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL.
These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL.
The GG genotype of the rs3776455 SNP in the MTRR gene was associated with a significantly reduced risk to ALL (p = 1.21×10(-3); OR = 0.55), which resulted mainly from the reduced risk to B-cell and hyperdiploid-ALL.
With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL.
Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12;21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to γ-glutamyl hydrolase (GGH) activity was lower in the t(1;19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes.
Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12;21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to γ-glutamyl hydrolase (GGH) activity was lower in the t(1;19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes.
Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12;21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to γ-glutamyl hydrolase (GGH) activity was lower in the t(1;19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes.
Global gene expression analyses revealed that five genes in the minimally 57.4 Mb gained region--B4GALT3, DAP3, RGS16, TMEM183A and UCK2--were significantly overexpressed in dup(1q)-positive ALLs compared with high hyperdiploid ALLs without dup(1q).
Somatic mutations of the X-linked transcription factor gene, GATA1, have been detected uniformly and exclusively in DS AMkL cases, which may lead to altered expression of GATA1 target genes and alter the metabolism of drugs including ara-C. Hyperdiploid acute lymphoblastic leukemia (ALL) cells with extra copies of chromosome 21, generate higher levels of the active methotrexate (MTX) metabolite, MTX polyglutamates.
Now, however, we can provide direct evidence of this from our identification of CD34+/CD19+ B-lineage progenitor cells with triploid chromosomes in the stored cord blood of an individual who subsequently developed hyperdiploid ALL.
Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+.
We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10<sup>-8</sup>), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10<sup>-8</sup>) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10<sup>-8</sup>), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10<sup>-8</sup>).
We examined three pairs of monozygotic twins, two concordant and one discordant for hyperdiploid ALL, for single-nucleotide polymorphism (SNP)-defined copy number alterations (CNAs), IGH/L plus TCR gene rearrangements and mutations in NRAS, KRAS, FLT3 and PTPN11 genes.
T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells.
Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12;21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to γ-glutamyl hydrolase (GGH) activity was lower in the t(1;19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes.