NPM1 Deletion Is Associated with Gross Chromosomal Rearrangements in Leukemia

Abstract

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 FindingsBone 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.

Topography, Clinical, and Genomic Correlates of 5q Myeloid Malignancies Revisited

“…Interestingly, in a recent study using 11 different 5q fluorescent in situ hybridization probes in 43 cases with isolated del(5q) deletions, the centromeric breakpoints always fell distally to RP11-80K5 (band 5q14.1), and only one of those patients had a deletion involving the NPM1 locus (band 5q35.1). 24 Although not strictly comparable to our WHO-defined 5q-syndrome cohort, those results support our definition of 5qSy-CRRs.…”

Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome

“…Moreover, in MDS and AML patients with unbalanced 5q translocation compared to those harboring an interstitial 5q deletion more additional chromosomal aberrations were observed and significantly more patients harbored a complex karyotype. La Starza et al () reported the occurrence of NPM1 deletion in 40% of patients with MDS and AML with 5q deletion and complex karyotype. In our cohort, patients with complex karyotype showed in 59.1% of MDS patients and 51.7% of AML patients an unbalanced 5q rearrangement, in which NPM1 located at 5q35 was deleted.…”

“…Deletions involving the centromeric and telomeric extremes of 5q affecting the described CRRs were associated with a more aggressive clinical course of MDS and AML (Jerez et al, ). Moreover, La Starza et al () had shown before in 145 patients with MDS and AML that telomeric breakpoints differ between cases with isolated 5q deletion and 5q loss with additional aberrations. Patients with additional aberrations showed a significantly higher rate of monoallelic loss of NPM1 , located on 5q35.1, than those with isolated 5q deletion.…”

Different boundaries characterize isolated and non-isolated 5q deletions in myelodysplastic syndromes and acute myeloid leukemias

“…3 We recently showed that telomeric breakpoints were significantly different in cases with isolated and non-isolated del(5q). Non-isolated del(5q) showed NPM1/5q35.1 monoallelic loss in 38 of 84 cases (45.2%) versus one of 43 (2.3%) of isolated del(5q) (Fisher's exact test P<0.001) 4 . Moreover, gross chromosomal anomalies and monosomies, as seen in high-risk MDS/AML phenotype, were significantly related to NPM1 haploinsufficiency.…”