A Fluorescence in Situ Hybridization Map of 6q Deletions in Acute Lymphocytic Leukemia

Abstract

With the objective of identifying candidate tumor suppressor genes, we used fluorescence in situ hybridization to map leukemia-related deletions of the long arm of chromosome 6 (6q). Twenty of 24 deletions overlapped to define a 4.8-Mb region of minimal deletion between markers D6S1510 and D6S1692 within chromosome 6 band q16. Using reverse transcription-PCR, we found evidence of expression in hematopoietic cells for 3 of 15 genes in the region (GRIK2, C6orf111, and CCNC). Comparison between our own and published deletion data singled out GRIK2 as the gene most frequently affected by deletions of 6q in acute lymphocytic leukemia (ALL). Sequence analysis of GRIK2 in 14 ALL cases carrying heterozygous 6q deletions revealed a constitutional and paternally inherited C to G substitution in exon 6 encoding for an amino acid change in one patient. The substitution was absent among 232 normal alleles tested, leaving open the possibility that heterozygous carriers of such mutations may be susceptible to ALL. Although low in all normal hematopoietic tissues, quantitative reverse transcription-PCR showed higher baseline GRIK2 expression in thymus and T cells than other lineages. Among T-cell ALL patients, 6q deletion was associated with a statistically significant reduction in GRIK2 expression (P ‫؍‬ 0.0001). By contrast, elevated GRIK2 expression was measured in the myelomonocytic line THP-1 and in one patient with common ALL. Finally, we detected significant levels of GRIK2 expression in prostate, kidney, trachea, and lung, raising the possibility that this gene may be protective against multiple tumor types.

Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization

“…We confirmed heterogeneous deletions of 6q as recurrent events in ALL. These findings concurred with a number of studies using FISH and loss of heterozygosity (LOH), which demonstrated several common regions of deletion involving 6q21-q23 (Jackson et al, 2000;Foroni et al, 2003;Sinclair et al, 2004), further highlighting the importance of this region in ALL pathogenesis while demonstrating that aCGH can be used to accurately delineate regions of CNA in ALL. Even though the cases in this study were highly selected for the absence of established chromosomal abnormalities, a small number were included from other patient subgroups, such as high hyperdiploid and ETV6-RUNX1 positive patients.…”

Novel Role of Prostate-Specific Membrane Antigen in Prostate Cancer Invasion and Metastasis

“…Ac-Asp + Glu or Met (18) One of the constant products of PSMA enzymatic reaction is glutamate, which might also be a potential modulator and functions through glutamate receptors. Glutamate receptors have been reported to be present in prostate and LNCaP cells as well (19,20). Alternatively, folates, which are produced as a by-product of this enzymatic reaction, could be a potential modulator for PSMA enzymatic activity.…”

Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study

“…29 Deletions involving 6q are otherwise quite rare in AML, being associated mainly with lymphoid malignancies. [63][64][65] As yet, the target gene(s) is unknown, and because no clear-cut minimally deleted segment was identified (Figure 4), it may prove difficult to identify the genes involved. The losses of 7p and gains of 7q often occurred together in DS-AML, as a consequence of i(7q).…”