Association of cis-Acting rs530 of the ETS2 Transcriptional Factor Gene with High-Risk Acute Myelogenous Leukemia (AML) and Allelic Expression Imbalance Assessment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2230-2230
Author(s):  
Il-Kwon Lee ◽  
Jeong-Hwa Choi ◽  
Hee Nam Kim ◽  
Yeo-Kyeoung Kim ◽  
Kyeong-Soo Park ◽  
...  
Keyword(s):  
High Risk ◽  
Secondary Structure ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Heterozygous Genotype ◽  
Factor Gene ◽  
Cis Acting ◽  
Increased Risk ◽  
Acute Myelogenous

Abstract We have previously implicated ETS2 in the etiopathogenesis of acute myeloid leukemia through case-control study by revealing that polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to acute myelogenous leukemia (AML). Two SNPs out of 7 genotyped sites, rs711 and rs530 were shown to be associated with increased risk to AML with the odds ratio (OR) of 1.76 (95% C.I. 1.2–2.5, p=0.0019) for rs711 and 1.67 (95% C.I. 1.3–2.2, p=0.0003) for rs530 relative to wild type genotypes respectively. Haplotype and linkage disequilibrium (LD) map was estimated, but haplotype association was not found with statistical significance. Korean LD structure was similar to Japanese LD, but least similarity was shown with LDs from African (Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants introduced in the sequence. Most dramatic change in the secondary structure was observed in the rs530 containing domain suggesting this variant of being cis-acting genetic variant. Real time Q-PCR and western blot analysis showed that expression of ETS2 decreased in individuals with heterozygous or mutant homozygous genotypes, showing most abundant expression with two wild type copies of rs530, less expression with the rare homozygous or heterozygous genotype. Sequencing cDNA of 55 heterozygous AML patients revealed mRNA expression imbalance in 13 cases (24%) effectively reverting heterozygous genotype to homozygous wild type mRNA species. The detection of a discrepancy between the mRNA alleles of rs530 clearly proves cis-acting effect of rs530. However there was not a case in 51 healthy control samples suggesting differing transcript levels derived from the two alleles of an autosomal gene is disease-specific phenomena. Taken together, our results suggest that two polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by inducing change in mRNA expression as a cis-acting variant.

Two Single Nucleotide Polymorphisms of the ETS2 Transcriptional Factor Gene Predispose Individuals to High-Risk Acute Myelogenous Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2729-2729
Author(s):  
Il-Kwon Lee ◽  
Jeong-Hwa Choi ◽  
Yeo-Kyeoung Kim ◽  
Hee Nam Kim ◽  
Kyeong-Soo Park ◽  
...  
Keyword(s):  
Transcription Factor ◽  
High Risk ◽  
Secondary Structure ◽  
Statistical Significance ◽  
Myelogenous Leukemia ◽  
International Hapmap Project ◽  
Nucleotide Polymorphisms ◽  
Factor Gene ◽  
Increased Risk ◽  
Polymorphic Variants

Abstract ETS2 (v-ets avian erythroblastosis virus E2 oncogene homolog 2) is a transcription factor located in the human chromosomal region 1q22.3 encoding a 56-kDa protein. In this study we carefully selected a set of haplotype-tagging SNPs (htSNP) and genotyped their frequencies in order to identify polymorphic variants that contributes to the inter-individual differences in susceptibility to disease phenotypes. Here we report polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to AML. Seven SNPs derived from genomic region of the ETS2 gene, rs1209953, rs3746882, rs2298560, rs457705, rs2070531, rs711 and rs5307 were genotyped to estimate allele frequency, haplotype block and linkage disequilibrium (LD) map. Among those rs711 and rs530 were shown to be associated with increased risk to AML with statistical significance. The odds ratio (OR) for rs711 and rs530 relative to wild type genotypes are 1.76 (95% C.I. 1.2–2.5, p=0.0019) and 1.67 (95% C.I. 1.3–2.2, p=0.0003) respectively. Cumulative frequencies of four common haplotypes are 72%, among which T-T-G-T-C-G-T was the most ancestral haplotype comprising 36% of total haplotypes. We also examined the possibility of haplotype association, but no association was found. When we compared LD map with LDs constructed from the International HapMap project, Korean LD map was similar to Japanese LD, but least similarity was shown with LDs from African(Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants sequence. Severe change in the secondary structure was observed in the rs530 containing domain suggesting this change might affects stability of mRNA. Real time Q-PCR and western blot revealed that expression of ETS2 decreased in a dosage-dependant manner, showing most abundant expression when homozygously T/T at rs530, least expression with the homozygous A/A and intermediate level of expression when the heterozygous genotype. Our results suggest that polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by altering the secondary structure of mRNA.

High-risk acute myelogenous leukemia: treatment today … and tomorrow

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 201-208 ◽  
Author(s):  
Gary J. Schiller
Keyword(s):  
High Risk ◽  
Acute Myelogenous Leukemia ◽  
Poor Response ◽  
Myelogenous Leukemia ◽  
Term Survival ◽  
Long Term Survival ◽  
Clinical Variables ◽  
Molecular Abnormalities ◽  
Acute Myelogenous

Abstract High-risk acute myelogenous leukemia (AML) constitutes a distinct subset of disease based on clinical and biological characteristics and comprises a significant percentage of all cases of adult AML. Biologic features such as distinct clonal cytogenetic and molecular abnormalities identify a subgroup of AML patients characterized by poor response to induction chemotherapy and poor long-term survival after treatment with consolidation chemotherapy. Clinical variables that predict for poor response include AML relapsed after less than 1 year of remission and AML characterized by resistance to conventional agents. We review here our understanding of the defining biologic subtypes of AML and discuss how adequate initial evaluation can be used to inform the choice of treatment. By defining high-risk biologic and clinical variables, a strong case can be made for treating patients with investigational agents, with treatment directed at distinct cytogenetic or molecular abnormalities. Allogeneic transplantation is the only form of therapy available outside of the setting of a clinical trial that may offer a chance for long-term survival for patients with high-risk AML.

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia

2020 ◽  
Vol 20 (4) ◽  
pp. 226-233.e1
Author(s):  
Benjamin K. Tomlinson ◽  
Molly M. Gallogly ◽  
Donna M. Kane ◽  
Leland Metheny ◽  
Hillard M. Lazarus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Acute Myelogenous Leukemia ◽  
Phase Ii Study ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Acute Myelogenous ◽  
Unfit Patients

scholarly journals Mutation of the p53 gene in human acute myelogenous leukemia

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1500-1507 ◽  
Author(s):  
JM Slingerland ◽  
MD Minden ◽  
S Benchimol
Keyword(s):  
Acute Myelogenous Leukemia ◽  
P53 Protein ◽  
Point Mutations ◽  
P53 Gene ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
P53 Expression ◽  
Coding Sequence ◽  
Acute Myelogenous ◽  
Blast Cells

Abstract Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.

Extended Study for Topotecan, Idarubicin, and Intermediate-Dose Cytarabine Combination Chemotherapy in Patients with Refractory or Relapsed Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4609-4609
Author(s):  
Yuri Kim ◽  
June-Won Cheong ◽  
Jin Seok Kim ◽  
In Hae Park ◽  
Sun Young Park ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Myelodysplastic Syndrome ◽  
Combination Chemotherapy ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Group 4 ◽  
Remission Duration ◽  
Acute Myelogenous ◽  
Intermediate Dose

Abstract The development of more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS) is a major concern in hematology. We previously reported a preliminary data that combination chemotherapy with topotecan, idarubicin, and intermediate dose cytarabine had a significant anti-leukemia activity and acceptable range of toxicity for the high-risk AML/MDS patients. In this study, we demonstrate an extended data for investigating larger number of patients with long-term follow-up of five years. The forty-seven patients were enrolled: 10 with primary refractory AML, 16 with AML in first relapse, 9 with AML in second relapse, and 12 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1–3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1–5, and topotecan 1.25 mg/m(2) over 24 hr on days 1–5. Median age of patients was 47 years (range 17–69 years). Patients with AML were categorized to high-risk (n=21), intermediate-risk (n=11), and low-risk (n=3) cyrogenetic group. All patients were evaluable for response: 23 (48.9%) achieved complete remission, 18 with AML (51.4%) and 5 with MDS (41.7%), respectively. The median remission duration and survival of patients with AML were 7 and 13 months, respectively. Median remission duration and survival of MDS patients was 10 and 15 months, respectively. Severe myelosuppression was observed in all patients, resulting in the fever or documented infections in 85.1% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 23 days (11–37 days) and for platelets > 20 x 10(9)/l 37 days (11–63 days). Reversible grade 3–4 toxicities included diarrhea (3 patients) and mucositis (13 patients). The relapsed AML patients (n=16) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1–2 years and receiving S1; group 3, first CR duration 0–1 years and receiving S1; and group 4, first CR duration 0–1 years and receiving S2, S3, or S4 after failing S1. The response rate of group 4 (33.3%) was significantly lower than that of other groups (P < 0.05). We conclude that combination chemotherapy with topotecan, idarubicin, and intermediate dose cytarabine is an effective salvage chemotherapy for high risk AML/MDS patients, and the first CR duration is a significant predictor for response.

Allogeneic Hematopoietic Cell Transplantation for Acute Myelogenous Leukemia in Remission - a Prospective Comparison of Three Different Donor Groups; Matched Sibling, Matched Unrelated, and Haploidentical Family Donors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4379-4379 ◽  
Author(s):  
Kyoo-Hyung Lee ◽  
Je-Hwan Lee ◽  
Jung-Hee Lee ◽  
Dae-Young Kim ◽  
Han-Seung Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Acute Myelogenous Leukemia ◽  
Graft Failure ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Matched Sibling

Abstract Allogeneic hematopoietic cell transplantation (HCT) from HLA-matched sibling (MS) or unrelated donors (MU) is a well-established treatment for patients with intermediate/high-risk acute myelogenous leukemia (AML) in remission. When HLA-matched donors are not available, however, use of haploidentical family (HF) donors for HCT remains controversial. Therefore, we performed a prospective study, where patients with AML in complete remission (CR) underwent allogeneic HCT according to the donor priority of MS, MU, or HF donors. Conditioning regimen for MS-HCT was busulfan (3.2 mg/kg • 4 days)-cyclophosphamide (60 mg/kg • 2 days) or, for patients >55 years or with co-morbidity, busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (1.5 mg/kg • 3 days). Patients undergoing MU- or HF-HCT received busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (3 mg/kg • 3 days) (Lee K-H et al; Blood 2011;118:2609-2617; Am J Hematol 2011;86:399-405). Ex-vivo T cell depletion was not performed. GVHD prophylaxis included cyclosporine plus a short course of methotrexate. Between January 2010 and December 2014, 244 patients enrolled. Of those, 16 patients were excluded from the analysis (12 patients relapsed before HCT; 3 with major protocol violation; and 1 with incomplete data). Of remaining 228 patients, 81 underwent HCT from MS donors, 90 from MU donors, and 57 from HF donors. The donors for MU-HCT were younger and more male-dominant than those for MS- or HF-HCT. The characteristics of patients and their donors were summarized in Table 1. Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P* Median age, yr (range) 48 (19-66) 43 (16-66) 46 (17-69) Sex, male/female 37/44 44/46 29/28 0.824 CR1/CR2 76/5 82/8 47/10 0.098 Chromosome risk,low**/intermediate/high/high-monosomal 6/57/10/5 4/65/16/3 2/40/7/5 0.751 Donor median age, yr (range) 45 (18-63) 28 (20-45) 29 (15-58) Donor age, yrup to 2526-45over 45 44136 29610 19326 0.000 Donor sex, male/female 46/35 76/14 36/21 0.000 Donor relation, parents/sibling/offspring 7/24/26 HLA allele mismatch/8 (GVH direction), 0/1/2/3/4 81/0/0/0 51/26/10/2/1 0/0/5/22/30 0.000 Graft, bone marrow/peripheral blood 28/53 0/90 0/57 0.000 Median nucleated cell count, •108/kg (range) 8.0 (0.9-19.0) 10.8 (4.1-31.4) 10.8 (5.1-19.3) Median CD34+ count, •106/kg (range) 4.9 (0.8-18.0) 8.0 (1.4-26.2) 6.4 (2.4-25.7) *by Chi-square test; **Twelve patients with AML of low-risk chromosomal abnormality included 6 patients in CR2, 3 with c-kit mutation, and 3 with persistent aml1-eto or cbf beta-myh11 after induction chemotherapy. The median follow-up duration of 164 survivors in the study was 34.7 months (range, 3.7-63.6) after HCT. The donor-group effect on the HCT outcomes was described in Table 2. Patients who underwent MS-HCT showed slightly slower neutrophil engraftment and higher incidence of chronic GVHD. Otherwise, in terms of disease recurrence, NRM, graft failure, EFS, and OS, there was no significant difference according to the donor-type. For AML recurrence, cytogenetic risk was an independent prognostic factors (P =0.003; hazard ratio of low-risk to; intermediate-risk, 1.42; high-risk, 2.53; high-risk with monosomal karyotype, 5.47). Table 1. MS-HCT (n=81) UD-HCT (n=90) HF-HCT (n=57) P Cumulative incidence ( 95% confidence interval)* AML recurrence 29% (19-40%) 26% (17-36%) 35% (20-51%) 0.785 Non-relapse mortality (NRM) 8% (3-16%) 7% (2%-16%) 11% (4-21%) 0.435 Graft failure 1% (0.1-6%) 6% (2-12%) 5% (1-13%) 0.293 ANC>500/uL median days (range) 100% 13 (9-20) 99%12 (10-45) 98% 12 (6-22) 0.049 Platelet>20,000/uL median days (range) 99% (86-100%) 14 (0-83) 97% (88-99%) 13 (0-77) 96% (83-99%) 14 (0-106) 0.352 Grades 2-4 acute graft-versus-host disease (GVHD) 12% (6-21%) 13% (7-21%) 23% (13-34%) 0.176 Moderate to severe chronic GVHD 39% (28-50%) 22% (13-30%) 23% (13-35%) 0.0452 4-year survival** Event-free (EFS) 63% 69% 54% 0.381 Overall (OS) 62% 74% 64% 0.077 *compared by Gray's method; **compared by log-rank test Our study showed that, despite heterogeneity of baseline donor characteristics (age and sex), conditioning regimen, and graft source (bone marrow vs. peripheral blood), overall post-transplant outcomes were similar among recipients from MS-, MU-, and HF-donors. Therefore, for patients with AML in CR but without an HLA-matched donor available, HCT from a haploidentical family member may be considered. Disclosures No relevant conflicts of interest to declare.

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