Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations

Micol, Jean-Baptiste; Duployez, Nicolas; Boissel, Nicolas; Petit, Arnaud; Geffroy, Sandrine; Nibourel, Olivier; Lacombe, Catherine; Lapillonne, Hélène; Étancelin, Pascaline; Figeac, Martin; Renneville, Aline; Castaigné, Sylvie; Leverger, Guy; Ifrah, Norbert; Dombret, Hervé; Preudhomme, Claude; Abdel-Wahab, Omar; Jourdan, Éric

doi:10.1182/blood-2014-04-571018

Cited by 106 publications

(112 citation statements)

References 22 publications

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“…35 Within CBF AML, ASXL1 and ASXL2 mutations were recently reported to occur exclusively in AML with t(8;21), but not in AML with inv (16). 19,20,36 The present study extends those findings. We performed extensive mutational analysis by HTS in 215 patients with CBF AML from 1 to 60 years.…”

Section: Discussionsupporting

confidence: 79%

“…FLT3-TKD, n (%) 28 (13) 24 (22) 4 (4) ,.001* FLT3-ITD, n (%) 14 (7) 3 (3) 11 (10) .028* FLT3 all, n (%) 41 (19) 26 (24) 15 (14) .083…”

Section: Gene Mutationsmentioning

confidence: 99%

“…ASXL1/2 mutations have been described in ;35% of t(8;21) AML but are absent in inv(16)AML. 19,20 Interestingly, ASXL2 mutations are not recurrent in subsets of AML other than t(8;21) AML, suggesting an important potential functional intersection between ASXL2 mutations and the RUNX1-RUNX1T1 fusion specifically. 21 Besides ASXL1/2 mutations, however, no other recurrent mutations specific to 1 or both CBF AML subsets are currently known.…”

Section: Introductionmentioning

confidence: 99%

“…ASXL2 sequencing was performed as previously described. 19 Notably, because of technical limitations, the mutation c.1934dupG in ASXL1 cannot be detected with PGM sequencing, justifying its systematic validation by Sanger sequencing as previously described. 19 In 1 case, this ASXL1 variant could not be verified by Sanger sequencing because of a low VAF (4%), but was retained by visual check of the reads (UPN 53).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

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195

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Key Points• Recurrent mutations in chromatin modifiers and cohesin were observed in t(8;21) AML, but not inv (16 . Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.

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Section: Discussionsupporting

confidence: 79%

“…FLT3-TKD, n (%) 28 (13) 24 (22) 4 (4) ,.001* FLT3-ITD, n (%) 14 (7) 3 (3) 11 (10) .028* FLT3 all, n (%) 41 (19) 26 (24) 15 (14) .083…”

Section: Gene Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

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195

186

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“…1 P atients with this chromosomal translocation are classified as having "favorable-risk" disease, but ,60% of them are actually cured by current treatment approaches. 2 Activating mutations in the KIT gene occur in approximately one-third of patients with t(8;21) and identify a subgroup with adverse outcomes.…”

mentioning

confidence: 99%

ASXL genes and RUNX1: an intimate connection?

Metzeler

2014

Blood

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In this issue of Blood, Micol et al report the discovery of mutations in the additional sex combs-like 2 (ASXL2) gene in about one-quarter of acute myeloid leukemia (AML) patients carrying the t(8;21) translocation. Based on this rationale, Micol et al performed whole-exome sequencing of 3 patients with t(8;21) AML, and identified 2 somatic mutations in the ASXL2 gene. In a validation cohort of 110 adult and pediatric patients with t(8;21), ASXL2 mutations were present in 23%, making ASXL2 the secondmost commonly mutated gene in this cytogenetic subgroup, behind KIT (see figure). ASXL2 mutations have previously been reported, although at a much lower frequency, in various solid tumors including cancers of the bladder, prostate, endometrium, pancreas, and breast. Recently, Huether and colleagues studied 1000 pediatric cancer genomes and found ASXL2 mutations in 7 patients, including 6 with AML and balanced chromosomal rearrangements affecting the core binding factor (CBF) genes.3 Micol and colleagues now extend this initial report by demonstrating that ASXL2 mutations are restricted to patients with the t(8;21) translocation, which leads to a RUNX1-RUNX1T1 gene fusion. In contrast, ASXL2 mutations were absent in patients with RUNX1 point mutations or in patients with inversion inv(16), causing rearrangement of the RUNX1 heterodimerization partner CBF b (CBFB). ASXL1 mutations were found in 10% of t(8;21) patients, and were mutually exclusive with ASXL2 mutations. Micol et al also investigated the prognostic relevance of ASXL gene mutations in t(8;21) AML. They observed no difference in overall survival between ASXL1-mutated, ASXL2-mutated, and wild-type patients (see figure). Cumulative incidence of relapse appeared to be higher in patients with ASXL1 or ASXL2 mutations, but this difference did not achieve statistical significance. These results are consistent with a previous study reporting that 11.5% of adult t(8;21) AML patients carry ASXL1 mutations, and that ASXL1-mutated patients have significantly shorter event-free survival, but similar overall survival compared with those with wild-type ASXL1.4 Of note, we and others have found that ASXL1 gene mutations associate with

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Acute Myeloid Leukaemia

2017

Leukaemia Diagnosis

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Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations

Cited by 106 publications

References 22 publications

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

ASXL genes and RUNX1: an intimate connection?

Acute Myeloid Leukaemia

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