Allelotype analysis of the myelodysplastic syndrome

Xie, Dong; Hofmann, Wolf Karsten; Mori, Naoki; Miller, Carl W.; Hoelzer, Dieter; Koeffler, H. Phillip

doi:10.1038/sj.leu.2401717

Cited by 15 publications

(12 citation statements)

References 30 publications

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“…Deletion in chromosome 1p36, containing the RUNX3 locus, is frequently observed in human leukemia cells. [19][20][21] Methylation of the RUNX3 promoter in AML has also been reported, 22 and RUNX3 expression is down-regulated in AML with t(8;21) or inv (16). 23,24 Collectively, our work represents the first direct evidence for the pivotal role of Runx3 in hematopoiesis.…”

Section: Resultssupporting

confidence: 55%

Runx3 deficiency results in myeloproliferative disorder in aged mice

Wang

Motoda

Satake

et al. 2013

Blood

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Section: Resultssupporting

confidence: 55%

Runx3 deficiency results in myeloproliferative disorder in aged mice

Wang

Motoda

Satake

et al. 2013

Blood

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“…This finding shows that pathogenetic mechanisms entailing loss of chromosome material may be operative in a fraction of MDS-related AML carrying an apparently normal karyotype. The data by Xie and colleagues 35 and by Mori and colleagues, 36 who used loss of heterozygosity (LOH) studies, support this argument, showing that DNA segments, located on chromosomes 1p36, 6q, 7p, 10p, 11q, 14q, may be deleted during the evolution of preleukemia into leukemia. Recently, LOH at 5q22.3-35.3, 11p15 and 19q12 loci was found in four out of 18 childhood AML cases with normal karyotype.…”

Section: Discussionmentioning

confidence: 91%

Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype

et al. 2002

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To better define the incidence and significance of cryptic chromosome lesions in acute myeloid leukemia (AML), fluorescence in situ hybridization (FISH) studies were performed in interphase cells and, when appropriate, in metaphase cells and in morphologically intact BM smears. Fifty-five adult de novo AML (group A) and 27 elderly AML or AML after myelodysplastic syndrome (AML-MDS) (group B) were tested using probes detecting the following anomalies: −5, −7, +8, deletions of 5q31, 7q31, 12p13/ETV6, 17p13/p53, 20q11. All the patients had a normal karyotype in more than 20 cells and tested negative for the common AML-associated fusion genes. No patient in group A was found to carry occult chromosome anomalies, whereas 8/27 patients in group B (P Ͻ 0.0001) showed 5q31 or 7q31 deletion (three cases each), a 17p13/p53 deletion or trisomy 8 (one case each) in 33-60% interphase cells. Metaphase cells showed only one hybridization signal at 5q31 (three cases) and 7q31 (one case), whereas two normal signals at 7q31 and chromosome 8 centromeres were seen in two patients with 7q deletion and trisomy 8 in interphase cells. The majority of blast cells (76-94%) carried the chromosome anomaly in all cases; erythroid involvement in a minority of cells was seen in three patients. In group B, the presence of occult chromosome anomalies was associated with exposure to myelotoxic agents in the workplace (5/8 cases vs 3/19, P = 0.026) and with a lower complete remission rate (0/6 patients vs 7/12, P = 0.024). We arrived at the following conclusions: (1) cryptic chromosome deletions in the order of a few hundred kb magnitude may be found in a fraction of elderly AML or MDS-related AML and not in de novo adult AML with normal karyotype; (2) these chromosome lesions are usually represented by submicroscopic rearrangements; (3) they display a specific pattern of cell-lineage involvement arguing in favor of their role in the outgrowth of the leukemic blast cells; (4) they are associated with a history of exposure to myelotoxic agents in the workplace and, possibly, with resistance to induction treatment.

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“…The LOH analysis was performed by PCR amplification of microsatellite sequences as described previously (Xie et al, 2000). The primers were obtained from Research Genetics (Huntsville, AL, USA) and are listed in Table 1.…”

Section: Loh Analysismentioning

confidence: 99%

RARβ2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia

et al. 2004

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Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem-cell disorder that leads to ineffective hematopoiesis, bone marrow fibrosis, and extramedullary hematopoiesis. The molecular mechanisms underlying the development of this myeloproliferative syndrome are currently unknown. In order to identify tumor suppressor genes that may be involved in the disease process, we performed an analysis for loss of heterozygosity (LOH) in CD34 þ cells from 29 patients with MMM. We observed a frequency of allelic loss on chromosomal arm 3p in 24% of cases. Detailed mapping of 3p revealed a distinct region of deletion at 3p24. Among the genes known to map within this region is the retinoic acid receptor-b (RARb2) gene. To determine whether RARb2 gene activity is diminished in this disease, we analysed its expression in CD34 þ cells from 17 patients with MMM using quantitative PCR. Our results indicate that expression of RARb2 is significantly decreased in 100% of patient samples compared to that in CD34 þ cells from 10 normal individuals. Since allelic loss at 3p24 occurs in o25% of patients, we investigated the contribution of epigenetic modifications to RARb2 inactivity. Using methylationspecific PCR, we found hypermethylation of RARb2 in 16 of 18 patients (89%), while the methylated form of the gene was absent in CD34 þ cells from nine normal individuals. Our results suggest that RARb2 acts as a tumor suppressor gene in MMM and that epigenetic changes are the most significant determinants of RARb2 gene activity in these patients.

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Allelotype analysis of the myelodysplastic syndrome

Cited by 15 publications

References 30 publications

Runx3 deficiency results in myeloproliferative disorder in aged mice

Runx3 deficiency results in myeloproliferative disorder in aged mice

Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype

RARβ2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia

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