NPM1 Deletion Is Associated with Gross Chromosomal Rearrangements in Leukemia

BACKGROUND: NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated. METHODOLOGY AND PRINCIPAL FINDINGS: Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the "5q- syndrome" but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p=0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion. CONCLUSIONS AND SIGNIFICANCE: NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML

Leukemias associated with Turner syndrome: Report of three cases and review of the literature

Cases of leukemia associated with Turner syndrome (TS) are rare. Here we report three TS patients with leukemia including one case of T-large granular lymphocyte leukemia (T-LGL), one rare case of coexistence of chronic lymphocytic leukemia(CLL) and idiopathic myelofibrosis (IMF) and one case of a patient with AML-M2 who received autologous stem cell transplantation (SCT). T-LGL and coexistence of CLL and IMF associated with TS are reported for the first time while the last case represents the first report of SCT in a leukemia patient with TS. Our cases and the limited data of previously reported leukemia patients with TS suggest that TS is not associated with a specific type of leukemia and that presentation, clinical course and response to treatment are similar to that of the non-TS leukemia patients. However, these patients may have a higher risk of liver complications. Interestingly, in the mosaic TS patients, the abnormal clones were restricted to the monosomic 45,X cells, indicating that the leukemic clones possibly originate from the monosomic cell line. Even in cases with no additional chromosome abnormalities, the ratio of X/XX cells in bone marrow cells was significantly increased compared to that in constitutional karyotype, indicating that monosomic cells possibly provide a survival advantage for leukemia cells or that reduced programmed cell death may be responsible for the expansion of the monosomic cells. (c) 2007 Elsevier Ltd. All rights reserved

Jumping translocations in hematological malignancies: a cytogenetic study of five cases

Jumping translocations (JT) are rare cytogenetic aberrations in hematological malignancies that include unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to two or more different recipient chromosomes in different cell lines. We report five cases associated with different hematologic disorders and JT to contribute to the investigation of the origin, pathogenesis, and clinical significance of JT These cases involve JT of 1q in a ease of acute myeloblastic leukemia (AML)-M1, a case of Burkitt lymphoma, and a case of BCR/ABL-positive acute lymphoblastic leukemia, as well as a JT of 13q in a case of AML-M5, and a JT of 11q segment in a case of undifferentiated leukemia. TO Our knowledge, with regard to hematologic malignancies, this study presents the first case of JT associated with AML-M1, the first case of JT involving 13q as a donor chromosome, and the first report of JT involving a segment of 11q containing two copies of the MLL gene, jumping on to two recipient chromosomes in each cell line and resulting in six copies of the MLL gene. Our investigation suggests that JT may not contribute to the pathogenesis but rather to the progression of the disease, and it demonstrates that chromosome band 1q10 as a breakpoint of the donor chromosome 1q is also implicated in AML, not. only in multiple myeloma as it has been known until now. (C) 2008 Elsevier Inc. All rights reserved

The G<i>⁵¹⁶</i>T <i>CYP2B6</i> Germline Polymorphism Affects the Risk of Acute Myeloid Leukemia and Is Associated with Specific Chromosomal Abnormalities

<div><p>The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The <i>CYP2B6</i> gene is subjected to a single-nucleotide polymorphism (G<i>⁵¹⁶</i>T) with heterozygotes (<i>GT</i>) and homozygotes (<i>TT</i>) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of <i>CYP2B6</i> G<i>⁵¹⁶</i>T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (<i>GT</i> and <i>TT</i>) in patients compared to the controls (<i>GT</i>:38.8% vs 29.8% and <i>TT</i>:9.3% vs 5.3% respectively) (<i>p</i><0.001). More specifically, a significantly higher frequency of <i>GT+TT</i> genotypes in <i>de novo</i> AML patients (46.6%) and an immensely high frequency of <i>TT</i> in secondary AML (<i>s</i>-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in <i>de novo</i> and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the <i>TT</i> genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of <i>TT</i> genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the <i>CYP2B6</i> polymorphism in AML susceptibility and suggest a possible role of the <i>CYP2B6</i> genetic background on the development of specific chromosomal aberrations.</p></div

Distribution of genotype and allele frequencies of <i>CYP2B6</i> G⁵¹⁶T polymorphism in patients and controls.

<p>*Genotypic distribution was available in 572 out of 619 samples.</p><p>p-value was evaluated after comparison between the <i>CYP2B6</i> genotypic distribution of patients and controls.</p

Genotype distribution and allele frequencies of <i>CYP2B6</i> G⁵¹⁶T polymorphism in AML patients according to karyotype and risk group based on Cytogenetics.

<p>ns: no significance.</p><p>*p-value was evaluated after comparison with our control population.</p