Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia

Tse, William; Meshinchi, Soheil; Alonzo, Todd A.; Stirewalt, Derek L.; Gerbing, Robert B.; Woods, William G.; Appelbaum, Frederick R.; Radich, Jerald P.

doi:10.1182/blood-2003-12-4347

Cited by 60 publications

(64 citation statements)

References 26 publications

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“…27 In another study, in 64 unselected pediatric AML samples, high AF1q expression was independently associated with poor survival. 28 Whether MLL-AF1q causes different expression levels of AF1q remains unknown; hence, further studies should address the underlying biology. Given the excellent outcome of this rare subgroup of patients, we suggest that direct screening for this translocation be incorporated in future pediatric AML treatment protocols and that patients with MLLAF1q should be allocated to the low-risk group (or treatment arm) of these protocols.…”

Section: Discussionmentioning

confidence: 99%

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Balgobind

Raimondi

Harbott

et al. 2009

Blood

405

342

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Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23-or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/ MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (؎ 5%), with large differences across subgroups (11% ؎ 5% to 92% ؎ 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] ‫؍‬ 0.1, P ‫؍‬ .004); t(6; 11)(q27;q23) (HR ‫؍‬ 2.2, P < .001); t(10; 11)(p12;q23) (HR ‫؍‬ 1.5, P ‫؍‬ .005); and t(10;11)(p11.2;q23) (HR ‫؍‬ 2.5, P ‫؍‬ .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis. (Blood. 2009;114:2489-2496)

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Section: Discussionmentioning

confidence: 99%

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Balgobind

Raimondi

Harbott

et al. 2009

Blood

405

342

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“…However, 8 out of 24 overexpressed genes did not belong to any of the above-mentioned functional groups. Although two genes, PDZK1 and MLLT11, were clearly relevant to cancer as both have been proposed as a candidate oncogene in diverse haematological malignancies (Busson-Le Coniat et al, 1999;Inoue et al, 2004;Tse et al, 2004), six were more difficult to relate to cancer. Three corresponded to genetic determinants of genetic syndromes (MTMR, DISC1, MTX1) and the three others bore functions with no obvious link to cancer (NENF, ENSA, TARBP1).…”

Section: Discussionmentioning

confidence: 99%

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

et al. 2006

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Chromosome 1 is involved in quantitative anomalies in 50 -60% of breast tumours. However, the structure of these anomalies and the identity of the affected genes remain to be determined. To characterise these anomalies and define their consequences on gene expression, we undertook a study combining array-CGH analysis and expression profiling using specialised arrays. Array-CGH data showed that 1p was predominantly involved in losses and 1q almost exclusively in gains. Noticeably, high magnitude amplification was infrequent. In an attempt to fine map regions of copy number changes, we defined 19 shortest regions of overlap (SROs) for gains (one at 1p and 18 at 1q) and of 20 SROs for losses (all at 1p). These SROs, whose sizes ranged from 170 kb to 3.2 Mb, represented the smallest genomic intervals possible based on the resolution of our array. The elevated incidence of gains at 1q, added to the wellestablished concordance between DNA copy increase and augmented RNA expression, made us focus on gene expression changes at this chromosomal arm. To identify candidate oncogenes, we studied the RNA expression profiles of 307 genes located at 1q using a home-made built cDNA array. We identified 30 candidate genes showing significant overexpression correlated to copy number increase. In order to substantiate their involvement, RNA expression levels of these candidate genes were measured by quantitative (Q)-RT -PCR in a panel of 25 breast cancer cell lines previously typed by array-CGH. Q -PCR showed that 11 genes were significantly overexpressed in the presence of a genomic gain in these cell lines, and 20 overexpressed when compared to normal breast.

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“…In cell lines overexpression of MLLT11 was associated with enhanced doxorubicininduced apoptosis, 78 whereas another study showed that high MLLT11 expression in AML was independently associated with poor survival. 79 By contrast, the t(10;11)(p12;q23) and t(6;11) (q27;q23) subgroup have poor prognosis, with a 5y-pEFS of 31 and 11% and a 5y-pOS of 45 and 22%, respectively. Also, adult AML patients with a t(6;11)(q27;q23) have a poor outcome.…”

Section: Mll-rearrangedmentioning

confidence: 98%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia

Abstract: The AF1q gene, a mixed-lineage leukemia fusion partner, is highly expressed in hematopoietic progenitor cells but has low expression in differentiated cells. We determined the expression of the

Cited by 60 publications

References 26 publications

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

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