Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23

Abstract

The clinical and biological features of acute myeloid leukemia (AML) with 11q23/MLL translocations are well known, but the characteristics of AML with partial tandem duplication of the MLL gene have not been explored comprehensively. In this study, MLL duplication was analyzed, in 81 AML patients without chromosomal abnormalities at 11q23, using Southern blotting, genomic DNA polymerase chain reaction (PCR), reversetranscription PCR and complementary DNA sequencing. Nine patients showed partial tandem duplication of the MLL gene, including eight (12%) of the 68 with normal karyotype. Seven patients showed fusion of exon 6/exon 2 (e6/e2), one, combination of differentially spliced transcripts e7/e2 and e6/e2, and the remaining one, combination of e8/e2 and e7/e2. Among the patients with normal karyotype, children aged 1 to 15 showed a trend to higher frequency of MLL duplication than other patients (2/5 or 40% vs 6/62 or 10%, P = 0.102). The patients with tandem duplication of the MLL gene had a significantly higher incidence of CD11b expression on leukemic cells than did those without in the subgroup of patients with normal karyotype (75% vs 28%, P = 0.017). There were no significant differences in the expression of lymphoid antigens or other myeloid antigens between the two groups of patients. In adults, the patients with MLL duplication had a shorter median survival time than those without (4.5 months vs 12 months, P = 0.036). In conclusion, partial tandem duplication of the MLL gene is associated with increased expression of CD11b on leukemic blasts and implicates poor prognosis in adult AML patients. The higher frequency of MLL duplication in children older than 1 year, than in other age groups, needs to be confirmed by further studies.

Trisomy 11 in myelodysplastic syndromes defines a unique group of disease with aggressive clinicopathologic features

“…AML with trisomy 11 has been shown to have a high frequency of MLL PTD [22][23][24] and interestingly, this MLL PTD likely occurs in the extra copy of chromosome 11. 25 Although the hypothesis that MLL PTD is leukemogenic has been challenged by its ubiquitous existence in healthy individuals and their life-long persistence, 26 recent observations and animal models have shown that MLL PTD disturbs normal hematopoiesis in a gain-of-function manner, as well as DNA hypermethylation and epigenetic silencing of the tumor suppressor gene.…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…This is in contrast to the frequency of MLL-PTD, which is equally low in pediatric AML, ranging from 1 to 10% depending on the screening method, 13,[37][38][39] as well as in adult AML, in the range of 5-10%. 37,[40][41][42][43][44][45][46][47] The different translocation partners of the rearranged MLL gene So far, more than 60 different fusion partners of MLL have been identified. Approximately 50% of pediatric AML cases with an MLL rearrangement consist of t(9;11)(p22;q23).…”

The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

“…Mutation analyses were performed on CEBPA in the only exon, 20 WT1 in exons 7, 8 and 9, 21 MLL-PTD that spanned exons 2-8, 22 JAK2 on V617F hot spot, 23 PTPN11 in exons 3 and 13, 24 RUNX1 in exons 3-8, 25 c-KIT in exons 8, 10, 11, 12 and 17, 26 RAS on codons 12 and 13, and 61 in exons 1 and 2, 27 FLT3-TKD on codon D835, 28 IDH1 on R132 hotspot, 14 ASXL1 in exon 12, 29 NPM1 on hotspot involving the C terminal portion of the transcript with a four nucleotides insertion between positions 960 and 961, 30 and FLT3-ITD in exon 14 31 as described previously. Mutations were detected by direct sequencing on the PCR products, and the sensitivity of each assay was about 15%.…”