AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Tang, Jih-Luh; Hou, Hsin‐An; Chen, Chien-Yuan; Liu, Chieh‐Yu; Chou, Wen‐Chien; Tseng, Mei‐Hsuan; Huang, Chih‐Fen; Lee, Fen‐Yu; Liu, Ming-Chih; Yao, Ming; Huang, Shang-Yi; Ko, Bor-Sheng; Hsu, Szu-Chun; Wu, Shang‐Ju; Tsay, Woei; Chen, Yao‐Chang; Lin, Liang-In; Tien, Hwei‐Fang

doi:10.1182/blood-2009-05-223784

Cited by 306 publications

(296 citation statements)

References 46 publications

(60 reference statements)

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“…For example, RUNX-1 and ASXL1 mutations are more common in males and are associated with a worse outcome in patients with AML. 33,34 Conversely, the presence of favorable mutations may also influence outcomes in female patients. For example, NPM1 mutations are associated with a favorable prognosis in the large group of patients with cytogenetically normal AML and are more frequent in females.…”

Section: Discussionmentioning

confidence: 99%

Nonbiological factors affecting survival in younger patients with acute myeloid leukemia

Borate

Mineishi

Costa

2015

Cancer

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BACKGROUNDProgress has been made in determining the biological variants of acute myelogenous leukemia (AML) and their prognostic implications. However, to the authors' knowledge, little is known regarding the impact of nonbiological factors (NBFs) on the survival of patients with AML.METHODSThe impact of NBFs (marital status, insurance status, county‐level income, and education) on survival was assessed along with biological factors (disease subtype, sex, age, and race/ethnicity) using a cohort of patients aged 19 to 64 years who were diagnosed with AML between 2007 and 2011 and reported to the Surveillance, Epidemiology, and End Results program registry (SEER 18).RESULTSThere were 5541 patients included. The median overall survival for the entire study population was 16 months. On multivariate analysis, an increased risk of death was independently linked to being a Medicaid beneficiary, uninsured, single, divorced, and residing in a county within the lower 3 quintiles of median household income. NBFs affected the risk of early (<2 months) and late mortality and their impact was confirmed among patients known to have received chemotherapy.CONCLUSIONSInsurance status, marital status, and county‐level income were found to independently affect the survival of younger patients with AML and should be integrated into outcome comparisons. Interventions are needed to mitigate the impact of social factors on survival among patients with AML. Cancer 2015;121:3877–3884. © 2015 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Nonbiological factors affecting survival in younger patients with acute myeloid leukemia

Borate

Mineishi

Costa

2015

Cancer

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“…15,24 A recent study on 470 adult AML patients found that RUNX1 mutations were a marker for a significantly lower complete remission rate and shorter disease-free and overall survival. 29 The CEBPA gene, located on chromosome band 19q13.11, encodes the transcription factor CCAAT/enhancer-binding protein-alpha which is essential for normal differentiation of granculocytes. 30 The involvement of CEBPA in leukemogenesis has been confirmed in many studies, with inactivating mutations reported predominately in AML M0, M1 and M2.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

Ernst¹,

Chase²,

Zoi³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundAberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms. Design and MethodsTo detect genomic copy number changes associated with such fusions, we performed a systematic search in 68 patients using custom designed, targeted, high-resolution array comparative genomic hybridization. Arrays contained 44,000 oligonucleotide probes that targeted 500 genes including all 90 tyrosine kinases plus downstream tyrosine kinase signaling components, other translocation targets, transcription factors, and other factors known to be important for myelopoiesis. ResultsNo abnormalities involving tyrosine kinases were detected; however, nine cytogenetically cryptic copy number imbalances were detected in seven patients, including hemizygous deletions of RUNX1 or CEBPA in two cases with atypical chronic myeloid leukemia. Mutation analysis of the remaining alleles revealed non-mutated RUNX1 and a frameshift insertion within CEBPA. A further mutation screen of 187 patients with myelodysplastic/myeloproliferative neoplasms identified RUNX1 mutations in 27 (14%) and CEBPA mutations in seven (4%) patients. Analysis of other transcription factors known to be frequently mutated in acute myeloid leukemia revealed NPM1 mutations in six (3%) and WT1 mutations in two (1%) patients with myelodysplastic/myeloproliferative neoplasms. Univariate analysis indicated that patients with mutations had a shorter overall survival (28 versus 44 months, P=0.019) compared with patients without mutations, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor. ConclusionsWe conclude that mutations of transcription and other nuclear factors are frequent in myelodysplastic/myeloproliferative neoplasms and are generally mutually exclusive. CEBPA, NPM1 or WT1 mutations may be associated with a poor prognosis, an observation that will need to be confirmed by detailed prospective studies. Haematologica 2010;95(9):1473-1480. doi:10.3324/haematol.2010 This is an open-access paper. Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

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“…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%.…”

Section: Mutation Analysismentioning

confidence: 99%

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

et al. 2010

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Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated þ 8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2 À /FLT3-ITD þ genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.

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AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Cited by 306 publications

References 46 publications

Nonbiological factors affecting survival in younger patients with acute myeloid leukemia

Nonbiological factors affecting survival in younger patients with acute myeloid leukemia

Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms

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

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