Drug Resistance in Childhood Acute Myeloid Leukemia

Styczyński, Jan

doi:10.2174/138920107780487465

Cited by 24 publications

(20 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Evidence has shown that AML patients who achieved CR had longer OS than non-CR patients [18–20], and chemo-resistance is the main reason for treatment failure in AML [25–27]. Hence, factors affect IC 50 of cytarabine may also influence prognosis of AML.…”

Section: Discussionmentioning

confidence: 99%

Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

et al. 2016

View full text Add to dashboard Cite

The prognosis of cytogenetically normal acute myeloid leukemia (CN-AML) varies greatly among patients. Achievement of complete remission (CR) after chemotherapy is indispensable for a better prognosis. To develop a gene signature predicting overall survival (OS) in CN-AML, we performed data mining procedure based on whole genome expression data of both blood cancer cell lines and AML patients from open access database. A gene expression signature including 42 probes was derived. These probes were significantly associated with both cytarabine half maximal inhibitory concentration values in blood cancer cell lines and OS in CN-AML patients. By using cox regression analysis and linear regression analysis, a chemo-sensitive score calculated algorithm based on mRNA expression levels of the 42 probes was established. The scores were associated with OS in both the training sample (p=5.13 × 10−4, HR=2.040, 95% CI: 1.364-3.051) and the validation sample (p=0.002, HR=2.528, 95% CI: 1.393-4.591) of the GSE12417 dataset from Gene Expression Omnibus. In The Cancer Genome Atlas (TCGA) CN-AML patients, higher scores were found to be associated with both worse OS (p=0.013, HR=2.442, 95% CI: 1.205-4.950) and DFS (p=0.015, HR=2.376, 95% CI: 1.181-4.779). Results of gene ontology (GO) analysis showed that all the significant GO Terms were correlated with cellular component of mitochondrion. In summary, a novel gene set that could predict prognosis of CN-AML was identified presently, which provided a new way to identify genes impacting AML chemo-sensitivity and prognosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

et al. 2016

View full text Add to dashboard Cite

show abstract

“…7 The main reason for treatment failure among patients with AML is resistance to therapy. [8][9][10] In addition, treatment with cytarabine is associated with a number of adverse side effects including myelosuppression, infections, mucositis, neurotoxicity, and acute pulmonary syndrome. 11 Cytarabine requires activation through intracellular phosphorylation to araC-triphosphate (ara-CTP).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Gamazon

Lamba

Pounds

et al. 2013

Blood

View full text Add to dashboard Cite

Key Points• A preclinical cell-based model identifies SNPs associated with cytarabine sensitivity that also associate with outcome in leukemia patients.• SNPs within the MCC gene were associated with cytarabine sensitivity in lymphoblastoid cell lines and leukemic blasts from patients.A whole-genome approach was used to investigate the genetic determinants of cytarabineinduced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7-to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10 25) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n 5 18) was significantly greater than expected by chance (P 5 .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P 5 1.31 3 10 26) and AA (vs GA or GG) genotype was associated with poorer OS (P 5 .015), likely as a result of greater treatment-related mortality (P 5 .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084. (Blood. 2013;121(21):4366-4376) IntroductionAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults and also occurs in children. Despite the genetic heterogeneity of the disease, patients have been treated for decades with similar combinations of cytarabine and anthracyclines with little improvement in overall survival (OS).1 Although the majority of patients (50%-60%) under 60 years achieve complete remission with traditional anthracycline-and cytarabine-based induction regimens, the long-term survival rates continue to be around 30% to 40% for adults and 60% for children. [2][3][4][5][6] Outcomes are worse for patients >60 years, with complete response rates in the range of 40% to 55% and poor long-term survival rates. 7 The main reason for treatment failure among patients with AML is resistance to therapy. [8][9][10] In addition, treatment with cytarabine is associated with a number of adverse side effects including myelosuppression, infections, mucositis, neurotoxicity, and acute pulmonary syndrome. 11Cytarabine requires activation through intracellular phosphorylation to araC-triphosphate (ara-CTP). The mechanism of action of cytarabine involves the incorporation of ara-CTP in place of deoxycytidine triphosphate, resulting in chain termination, blocking DNA and RNA synthesis and causing leukemic cell de...

show abstract

“…Cytarabine is an antimetabolite and the mainstay of treatment for acute myeloid leukemia (AML) [6]. In some AML patients, resistance to cytarabine is a major reason for treatment failure and in others, cytarabine is associated with several adverse side effects, including myelosuppression and neurotoxicity [15]–[19]. In a study by the Children's Oncology Group of pediatric patients with AML, patients with African ancestry had significantly worse survival compared with patients of exclusively European ancestry [20].…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

et al. 2011

View full text Add to dashboard Cite

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.

show abstract

Drug Resistance in Childhood Acute Myeloid Leukemia

Cited by 24 publications

References 98 publications

Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

Contact Info

Product

Resources

About