Evaluation of CDCP1 (CD318) and endoglin (CD105) expression as prognostic markers in acute myeloid leukemia

2021 ◽  
pp. 1-12
Author(s):  
Huda F. Ebian ◽  
Dina R. Issa ◽  
Amira S. Al-Karamany ◽  
Rasha L. Etewa ◽  
Hanaa M. El Maghraby ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Poor Response ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Cub Domain ◽  
Poor Outcomes ◽  
Wbc Count ◽  
Acute Myeloid

BACKGROUND: The most commonly used prognostic factors in acute myeloid leukemia (AML) are cytogenetic, molecular, and morphological markers. However, AML prognosis is still unfavorable particularly in adults. So, further reliable markers are urgently needed to improve the risk stratification and treatment decisions. CUB domain-containing protein 1 (CDCP1; CD318) and endoglin (CD105) are new markers correlated with poor prognosis in different solid tumors, but their role in AML prognosis is not fully evaluated. OBJECTIVES: This work aimed to evaluate the prognostic role of CD318 and CD105 in AML and their impact on the outcomes. METHODS: Sixty-five newly diagnosed AML patients were included in this study. CD318 and CD105 expression was assessed by quantitative real-time polymerase chain reaction. Patients were followed up for ∼ 2 years to evaluate the prognostic impact of gene expression on the outcomes. RESULTS: Patients with high CD318 and CD105 showed higher white blood cell (WBC) count, M2 subtype, poor cytogenetic risk, reduced complete remission, and a greater number of deaths compared to low CD318 and CD105. CD318 was correlated with CD105, and both were correlated with WBC count, bone marrow blasts, and peripheral blood blasts. After a follow-up period of up to 24 months, relapse-free survival for high CD318 and CD105 was significantly different (42.1% and 52.6% vs. 64.5% and 58.1% for low CD318 and CD105, respectively). Survival was worse in patients with high CD318 and CD105, as the mean survival time was 13.9 and 13.3 months compared to 24 and 22.7 months in low CD318 and CD105, respectively. CONCLUSIONS: CD318 and CD105 are upregulated in AML patients. Their overexpression was associated with poor response to treatment and poor outcomes. Therefore, CD318 and CD105 can be useful prognostic markers in AML.

Role of Gene Mutations in Adult Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3373-3373
Author(s):  
Sheng-Chieh Chou ◽  
Jih-Luh Tang ◽  
Liang-In Lin ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 3373 Poster Board III-261 Purpose Several gene mutations had been found to have clinical implications in patients with acute myeloid leukemia (AML), especially in those with normal karyotype. However, the role of such gene mutations for AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) was unclear and inconclusive. We retrospectively evaluated the prognostic impact of 8 gene mutations in adult AML patients undergoing allo-HSCT. Materials & Methods From 1995 to 2007, a total of 463 consecutive adult patients with de novo non-M3 AML had comprehensive gene mutation analyses at the National Taiwan University Hospital. Three hundred and twenty five patients who received conventional induction chemotherapy were enrolled in this study. Those who received only low dose chemotherapy or palliative treatment were excluded. The genetic alterations analyzed included NPM1, FLT3/ITD, FLT3/TKD, CEBPA, AML1/RUNX1, RAS, MLL/PTD, and WT1. The clinical implication of these genetic alterations in the patients receiving allo-HSCT was analyzed, and the result was compared with that in patients without allo-HSCT. Results The clinical characteristics in the patients receiving allo-HSCT (n=100) and those without (n=225) were similar with the exception of age, being younger in the former group (35.4 years vs. 49.5 years p<0.001). In univariate analysis, older age (Age > 45 years), higher initial WBC count (WBC>50K/μL), elevated LDH level, unfavorable karyotype, FLT3/ITD, mutations of AML1/RUNX1 were significantly associated with poorer overall survival (OS) in patients not receiving allo-HSCT; While NPM1mut/FLT3ITDneg and CEBPA mutations served as significantly good prognostic indicators. In multivariate analysis, age, WBC count, karyotype, FLT3/ITD, AML1/RUNX1, CEBPA and NPM1mut/FLT3ITDneg remained to be independent prognostic factors in non-allo-HSCT patients. However, in patients receiving allo-HSCT, only unfavorable karyotype and disease status (refractory or remission) at the time of transplantation were associated with poorer OS both in univariate and multivariate analyses. The similar prognostic impact of FLT3/ITD, CEBPA, AML1/RUNX1 and NPM1 on OS was not seen in patients receiving allo-HSCT. Furthermore, in contrast to its poor prognostic impact in non-allo-HSCT patients, mutation of AML1/RUNX1 was a significant good prognostic factor for relapse free survival (p=0.046), although not for OS, in allo-HSCT group. Conclusion FLT3/ITD, mutations of AML1/RUNX1, CEBPA and NPM1 have great prognostic implication for OS in AML patients not receiving allo-HSCT. However, their impact on OS is ameliorated in patients receiving allo-HSCT. The results need to be confirmed by further studies on more patients. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Isocitrate Dehydrogenase Enzyme Isoforms 1 and 2 Mutations in Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

2010 ◽  
Vol 28 (23) ◽  
pp. 3717-3723 ◽  
Author(s):  
Nicolas Boissel ◽  
Olivier Nibourel ◽  
Aline Renneville ◽  
Claude Gardin ◽  
Oumedaly Reman ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Dehydrogenase Enzyme ◽  
Induction Failure ◽  
Wbc Count ◽  
French Association ◽  
Acute Myeloid

Purpose Recently, whole-genome sequencing in acute myeloid leukemia (AML) identified recurrent isocitrate dehydrogenase enzyme isoform (IDH1) mutations (IDH1m), previously reported to be involved in gliomas as well as IDH2 mutations (IDH2m). The prognosis of both IDH1m and IDH2m in AML remains unclear. Patients and Methods The prevalence and the prognostic impact of R132 IDH1 and R172 IDH2 mutations were evaluated in a cohort of 520 adults with AML homogeneously treated in the French Acute Leukemia French Association (ALFA) -9801 and -9802 trials. Results The prevalence of IDH1m and IDH2m was 9.6% and 3.0%, respectively, mostly associated with normal cytogenetics (CN). In patients with CN-AML, IDH1m were associated with NPM1m (P = .008), but exclusive of CEBPAm (P = .03). In contrary, no other mutations were detected in IDH2m patients. In CN-AML patients, IDH1m were found in 19% of favorable genotype ([NPM1m or CEBPAm] without fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ITD]) and were associated with a higher risk of relapse (RR) and a shorter overall survival (OS). Favorable genotype in CN-AML could thus be defined by the association of NPM1m or CEBPAm with neither FLT3-ITD nor IDH1m. In IDH2m CN-AML patients, we observed a higher risk of induction failure, a higher RR and a shorter OS. In multivariate analysis, age, WBC count, the four-gene favorable genotype and IDH2m were independently associated with a higher RR and a shorter OS. Conclusion Contrarily to what is reported in gliomas, IDH1m and IDH2m in AML are associated with a poor prognosis. Screening of IDH1m could help to identify high-risk patients within the subset of CN-AML with a favorable genotype.

scholarly journals Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 436 ◽  
Author(s):  
Victor Pallarès ◽  
Montserrat Hoyos ◽  
M. Chillón ◽  
Eva Barragán ◽  
M. Prieto Conde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Markers ◽  
Response To Treatment ◽  
Intermediate Risk ◽  
Patient Subgroup ◽  
Acute Myeloid

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment.

Prognostic Impact of Wilms Tumor 1 Single Nucleotide Polymorphism rs16754 In Older Patients with Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2701-2701
Author(s):  
Aline Renneville ◽  
Nicolas Boissel ◽  
Nathalie Helevaut ◽  
Olivier Nibourel ◽  
Christine Terré ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Gene Mutations ◽  
Minor Allele ◽  
Prognostic Impact ◽  
Single Nucleotide ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 2701 The Wilms tumor 1 (WT1) gene, located at chromosome band 11p13, encodes a transcriptional regulator involved in normal hematopoietic development. The role of WT1 in acute myeloid leukemia (AML) has been underlined by the finding of WT1 overexpression in most AML cases and WT1 gene mutations in approximately 10% of AML patients. Recently, the minor allele of the silent Arg301 single nucleotide polymorphism (SNP) (rs16754), which is a 903A>G substitution in WT1 exon 7, was suggested to predict a favorable prognosis in adult patients with cytogenetically normal (CN) acute myeloid leukemia (AML). In contrast, no prognostic impact of this SNP was found in another study performed in pediatric AML. Our aim was to evaluate the frequency, the main associated features and the prognostic significance of WT1 SNP rs16754 in elderly patients with AML. Diagnostic bone marrow or peripheral blood samples were analyzed from 266 patients (age 50 to 70 years) with previously untreated de novo AML included in the French ALFA-9801 trial. WT1 SNP rs16754 and gene mutations of NPM1, CEBPA, FLT3 (internal tandem duplication, ITD), WT1 (exon 7 and 9), IDH1 and IDH2 (exon 4) were screened on genomic DNA by direct sequencing and fragment-length analysis for the detection of small insertion/deletion. The minor allele of WT1 SNP rs16754 was found in 85 (32%) out of 266 cases. Patients heterozygous or homozygous for minor allele (WT1AG or WT1GG) and patients homozygous for the major allele (WT1AA) did not significantly differ in terms of age, gender, white blood cell (WBC) count, FAB subtypes, cytogenetic categories, and gene mutations when those mutations are considered separately. However, among CN-AML, the frequency of the favorable genotype defined by the presence of NPM1 mutation or CEBPA mutation without neither FLT3-ITD nor IDH1 mutation was significantly lower in patients with at least one minor allele than in patients with two major alleles (5% vs 23% of CN-AML, p=0.02). In univariate analysis, complete remission rate was found similar between patients with at least one minor allele and patients with two major alleles (76% vs 75%, p=0.88). Patients with at least one minor allele tended to have a shorter median delay to relapse (7 vs 12.2 months, p=0.06) and had a significantly shorter overall survival compared to patients with the two major alleles (5-year OS, 14% vs 26%, p=0.02). In the subset of CN-AML (n=113), the presence of at least one minor allele was also associated with a shorter median delay to relapse (6.9 vs 12.5 months, p=0.02) but only a trend regarding overall survival was observed (5-year OS, 17% vs 30%, p=0.1). In multivariate analysis considering age, WBC count, cytogenetics (favorable, intermediate and unfavorable categories) as covariates, WT1 SNP rs16754 status was found to be an independent prognostic factor for relapse risk (HR 1.56, 95% CI 1.06 to 2.30, p=0.03) and overall survival (HR 1.54, 95% CI 1.08 to 2.20, p=0.02). Thus, in our cohort of older AML patients, the minor allele of WT1 SNP rs16754 appears to confer a relatively poor prognosis, which is in contradiction to what has been reported so far. Overall, our data suggest that WT1 SNP rs16754 is an interesting marker that may contribute to refine prognosis in AML, at least in this age group of patients. Further investigations are needed to clarify the relationship between WT1 SNP rs16754 and treatment outcome in AML and elucidate the biological effects of this SNP. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dysregulation of CCAAT/enhancer binding protein-alpha (CEBPA) expression in the bone marrow of acute myeloid leukemia patients

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Naglaa M. Hassan ◽  
Fadwa Said ◽  
Roxan E. Shafik ◽  
Mona S. Abdellateif
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Binding Protein ◽  
Response To Treatment ◽  
Pathological Features ◽  
Poor Prognostic Factor ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by accumulation of different types of mutations commonly the CCAAT/enhancer binding protein-alpha (CEBPA). However, the dysregulations of CEBPA expression in AML is still a debatable issue. The aim of the current study was to assess CEBPA gene expression in bone marrow (BM) aspiration specimens of 91 AML patients, compared to 20 control donors of bone marrow transplantation (BMT), using RT-PCR. Data were correlated with patients’ clinico-pathological features, response to treatment, progression-free survival (PFS), and overall survival (OS) rates. Results There was overexpression of CEBPA gene in AML patients compared to normal control [1.7 (0.04–25.6) versus 0.17 (0–4.78), respectively, P < 0.001]. Upregulation of CEBPA expression associated significantly with increased BM hypercellularity, total leucocyte counts, peripheral blood blast cell count, and poor PFS (P < 0.001, 0.002, 0.001, and 0.013, respectively). There was no significant association between CEBPA expression and any other relevant clinico-pathological features or OS rates (P = 0.610) of the patients. ROC analysis for biological relevance of CEBPA expression with AML showed that sensitivity and specificity of CEBPA expression at a cut-off value of 0.28 are 92.3% and 78.6%, respectively (P < 0.001). All patients who had CEBPA overexpression and mutant FLT3 showed BM hypercellularity, adverse cytogenetic risk, increased TLC, and PB blast cells count (P = 0.007, P < 0.001, 0.016, and 0.002, respectively). Conclusion CEBPA overexpression could be used as a genetic biological marker for AML diagnosis, as well as a poor prognostic factor for disease progression. It has no impact on OS rates of the patients.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

No Prognostic Impact of the WT1 Gene Single Nucleotide Polymorphism rs16754 in Pediatric Acute Myeloid Leukemia

2010 ◽  
Vol 28 (28) ◽  
pp. e523-e526 ◽  
Author(s):  
Iris H.I.M. Hollink ◽  
Marry M. van den Heuvel-Eibrink ◽  
Martin Zimmermann ◽  
Brian V. Balgobind ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Wt1 Gene ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pediatric Acute Myeloid Leukemia ◽  
Gene Single Nucleotide Polymorphism ◽  
Acute Myeloid

scholarly journals Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD

Haematologica ◽  
2011 ◽  
Vol 96 (9) ◽  
pp. 1310-1317 ◽  
Author(s):  
H. J. M. de Jonge ◽  
P. J. M. Valk ◽  
E. S. J. M. de Bont ◽  
J. J. Schuringa ◽  
G. Ossenkoppele ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Blood Cell ◽  
Cell Count ◽  
White Blood Cell Count ◽  
White Blood Cell ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Blood Cell Count ◽  
Acute Myeloid
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