High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations

Kühn, Michael W.M.; Radtke, Ina; Bullinger, Lars; Goorha, Salil; Cheng, Jinjun; Edelmann, Jennifer; Gohlke, Juliane; Su, Xiaoping; Paschka, Peter; Pounds, Stanley; Krauter, Jürgen; Ganser, Arnold; Quessar, Asmaa; Ribeiro, Raul C.; Gaidzik, Verena I.; Shurtleff, Sheila; Krönke, Jan; Holzmann, Karlheinz; Ma, Jing; Schlenk, Richard F.; Rubnitz, Jeffrey E.; Döhner, Konstanze; Döhner, Hartmut; Downing, James R.

doi:10.1182/blood-2011-09-380444

Cited by 68 publications

(90 citation statements)

References 50 publications

(83 reference statements)

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“…Interestingly, the E1-E5 region is closely matched to a previously reported location of recurrent focal amplification seen previously in ;3% of AML cases ( Fig. 4C; Radtke et al 2009;Kuhn et al 2012). We observed a trend that The Cancer Genome Atlas (TCGA) tumor samples harboring genomic amplifications 39 of MYC (not containing MYC itself) tended to have higher MYC mRNA levels (Supplemental Fig.…”

Section: Brg1 Occupies a Cluster Of Lineage-specific Enhancers (E1-e5supporting

confidence: 65%

“…An important observation in this study is that previously described focal amplifications at 8q24.21 closely match the position of the E1-E5 Myc enhancers (Radtke et al 2009;Kuhn et al 2012). These amplifications are highly focal (80-500 kb), with most lacking any proteincoding genes.…”

Section: Discussionmentioning

confidence: 54%

“…However, we note that only one of the nine focal amplifications seen in this AML cohort would be expected to contain the full-length CCDC26 transcript (Supplemental Fig. 21), and this RNA does not appear to be conserved in mouse cells (Radtke et al 2009;Kuhn et al 2012; data not shown). While several mechanistic possibilities exist for how amplifications at 8q24.21 promote leukemia, our observations raise the possibility that such events expand the enhancer repertoire at the Myc locus, which would drive elevated Myc expression to promote leukemogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…4A,B; Rada-Iglesias et al 2011). The strong enrichment of Brd4 occupancy at these sites classifies these elements as a ''super-enhancer,'' using the criteria of (Radtke et al 2009;Kuhn et al 2012). The labels indicate sample IDs used in the prior studies.…”

Section: Brg1 Occupies a Cluster Of Lineage-specific Enhancers (E1-e5mentioning

confidence: 99%

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Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

et al. 2013

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Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in~3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.

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Section: Brg1 Occupies a Cluster Of Lineage-specific Enhancers (E1-e5supporting

confidence: 65%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Brg1 Occupies a Cluster Of Lineage-specific Enhancers (E1-e5mentioning

confidence: 99%

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Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

et al. 2013

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“…This recommendation could nonetheless evolve if a better characterization of CBF-AML risk heterogeneity could be demonstrated using refined high-resolution genomic analysis. 31,32 Comparisons were based on cause-specific hazard Cox models, stratified on treatment arm and CBF subset when applicable, and the 12 patients who received allogeneic SCT in first hematological CR were censored at SCT time.…”

Section: Discussionmentioning

confidence: 99%

Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia

Jourdan

Boissel

Chevret

et al. 2013

Blood

304

189

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Key Points• In adult patients with core binding factor AML, intensified induction is not associated with a better outcome in the context of intensive postremission therapy.• Minimal residual disease, rather than KIT or FLT3 gene mutations, should be used to identify core binding factor AML patients at higher risk of relapse.Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P 5 .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www. clinicaltrials.gov as #NCT 00428558. (Blood. 2013;121(12):2213-2223

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A genome‐wide single‐nucleotide polymorphism‐array can improve the prognostic stratification of the core binding factor acute myeloid leukemia

Huh¹,

Kim²,

Jung³

et al. 2012

American J Hematol

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on behalf of AML/MDS working party, Korean Society of Hematology Core binding factor (CBF) AML with the D816 C-KIT gene mutation demonstrate inferior treatment outcomes. However, the remaining cases without the D816 C-KIT mutation imply a requirement of more sophisticated dissection of the patients according to their prognosis. In this study, we analyzed the prognostic value of a single nucleotide polymorphism array (SNP-A) based karyotyping combined with metaphase cytogenetics (MC) to facilitate further stratification of CBF AML patients. A total of 98 CBF AML patients were included and genome-wide Human SNP 6.0 Arrays (Affymetrix) were performed using marrow samples taken at diagnosis. Overall, 40 abnormal lesions were identified in 25 patients (26%). Survival of the patients with the abnormal lesion(s) detected by SNP-A and/or MC was worse than those without lesions in terms of the 2-year overall survival (OS; 57.5% vs. 76.4%, P 5 0.028), event-free (EFS; 45.7% vs. 66.2%, P 5 0.072), and leukemia-free survival (LFS; 49.0% vs. 77.4%, P 5 0.015), specially in the subgroup with inv(16)/t(16;16) (40.9% vs. 80.2% OS, P 5 0.040) and in the subgroup without the D816 C-KIT mutation (61.6% vs. 82.7% OS, P 5 0.038). Multivariate analysis confirmed the prognostic impact of the abnormal SNP-A and/or MC lesion on EFS (HR 2.011, P 5 0.047), and LFS (HR 3.231, P 5 0.005) in the overall CBF AML. This study suggests that the combined use of SNP-A with MC in the CBF AML can provide important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without the D816 C-KIT mutation. Am. J. Hematol. 87:961-968, 2012. V

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High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations

Cited by 68 publications

References 50 publications

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation

Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia

A genome‐wide single‐nucleotide polymorphism‐array can improve the prognostic stratification of the core binding factor acute myeloid leukemia

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