Genetic alterations and their clinical implications in older patients with acute myeloid leukemia

Tsai, Cheng‐Hong; Ha, Hou; Tang, Jih-Luh; Cy, Liu; Lin, Chang-Ping; Chou, Wen‐Chien; Mh, Tseng; Chiang, Yi-Te; Kuo, Yueh‐Hsiung; Liu, MC; Liu, Cheng Wei; Li, Lin; Tsay, Woei; Yao, Ming; Cc, Li; Huang, Shang-Yi; Ko, Bor-Sheng; Sc, Hsu; Cy, Chen; Ct, Lin; Sj, Wu; Tien, Hwei‐Fang

doi:10.1038/leu.2016.65

Cited by 105 publications

(108 citation statements)

References 58 publications

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“…The underlying reason might be that IDH2 but not IDH1 mutations were associated with older age . Recently, several other genetic alterations like TP53 , RUNX1 and ASXL1 mutations were found to be more prevalent in the elder population . However, we did not observe these genes as commonly mutated genes, the reason might be a difference in population.…”

Section: Discussioncontrasting

confidence: 68%

“…Because European LeukemiaNet (ELN) genotype was proposed as a standardized classification in the elderly patients with CN‐AML, we used ELN genotype but not individual genes ( FLT3 ‐ITD, NPM1 and CEBPA ) as a potential predictor in the multivariate models. To establish precision medicine for every patient, previous studies utilized 8–10 genes to classify patients into different prognostic groups . In fact, the genetic testing should have a short turnaround time, inexpensive and reliable.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Wang

et al. 2017

Intl Journal of Cancer

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Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk-stratification, and present cytogenetically normal AML (CN-AML). To develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by Sanger sequencing. The top 6 genes were NPM1, FLT3-ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. In addition, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3-ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event-free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN-AML.

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Section: Discussioncontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Wang

et al. 2017

Intl Journal of Cancer

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“…7 We adopted Kaplan–Meier estimation to plot survival curves, and used log-rank tests to examine the difference between groups. The variables including age, 28 white blood cell counts at diagnosis, karyotype, NPM1/FLT3- ITD , CEBPA , RUNX1 , WT1 , ASXL1, IDH2, DNMT3A, TP53 and splicing factors mutations were used as covariates in multivariate analysis. Relative risk and 95% confidence interval were estimated by Cox proportional hazards regression models to determine independent risk factors associated with survival in multivariate analyses.…”

Section: Methodsmentioning

confidence: 99%

Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia

Lin

et al. 2017

Blood Cancer J.

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Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.

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“…PTPN11 is also frequently mutated in secondary acute myeloid leukemia (AML) [19], relapsed pediatric AML [20] and acute lymphoblastic leukemia (ALL) [21]. The frequency of PTPN11 mutations in AML is higher in patients older than 60yrs [22] and also has prognostic significance. Secondary AML patients carrying mutations in PTPN11 show rapid disease progression and reduced overall survival [19].…”

Section: Shp2 In Leukemogenesismentioning

confidence: 99%

Role of SHP2 in hematopoiesis and leukemogenesis

Pandey¹,

Saxena²,

Kapur

2017

Current Opinion in Hematology

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Purpose of review SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it. Recent findings Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized. The review will discuss the newly discovered role of SHP2 in lineage specific differentiation. Recently, a non-cell autonomous role of oncogenic SHP2 has been reported in which activated SHP2 was shown to alter the bone marrow microenvironment resulting in transformation of donor derived normal hematopoietic cells and development of myeloid malignancy. From being considered as an ‘undruggable’ target, recent development of allosteric inhibitor has made it possible to specifically target SHP2 in receptor tyrosine kinase driven malignancies. Summary SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and micro-environmental effects. However a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic.

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Genetic alterations and their clinical implications in older patients with acute myeloid leukemia

Cited by 105 publications

References 58 publications

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia

Role of SHP2 in hematopoiesis and leukemogenesis

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