Expression profiling of some Acute Myeloid Leukemia - associated markers to assess their diagnostic / prognostic potential

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies with individual cases showing wide variations in response to treatment. Pre-treatment karyotype analysis may be used to stratify cases into one of three prognostic classes: favorable, intermediate or adverse. Favorable karyotypes, t(15;17), t(8;21) and inv(16), are associated with the presence PML-RARα, AML1-ETO and CBFβ-MYH11 gene rearrangements respectively. The adverse cytogenetic abnormalities are monosomy 5, monosomy 7, deletion of chromosome 5q, abnormalities of chromosome 3q and a complex karyotype. All remaining abnormalities are associated with an intermediate prognosis. Approximately 5–10% of cases cannot be stratified due to failure of cytogenetic analysis. Cryptic gene rearrangements, which cannot be detected by karyotyping, may lead to assignment of cases to incorrect prognostic classes. These problems may result in sub-optimal or over-treatment of patients. Using an artificial neural network-based analysis of HOX gene expression profiles generated by real-time quantitative PCR (RT-QPCR) we have previously shown that the favorable and intermediate cytogenetic classes are characterised by low HOXA5 (Ct value > 29.5) and high HOXB3 (Ct value < 25) expression respectively (Blood2006; 108: Abstract 2318). We have now measured HOXA5 and HOXB3 expression levels by RT-QPCR in a fresh set of 78 newly diagnosed cases of AML (31 favorable, 38 intermediate and 9 adverse karyotypes as determined by conventional cytogenetic analysis). All 31 cases with favorable cytogenetics had HOXA5 Ct values > 29.5 with twenty-nine (93.5%) having Ct values > 33. Therefore, using a HOXA5 Ct ≥; 33 to define membership of the favorable prognostic class and HOXA5 Ct < 33 to define membership of a non-favorable class, 72 cases (92.3%) were correctly assigned (29 favorable and 43 non-favorable). Of the 4 cases with non-favorable cytogenetics, originally misclassified by HOXA5 expression profiling, two were subsequently found to have cryptic rearrangements of PML-RARα and therefore should have been included within the favorable group. This increased the percentage of cases correctly assigned by HOXA5 expression profiling alone to 94.9%. We also found that within the favorable group, AML with t(15;17) or t(8;21) was characterized by low expression of HOXB3 (Ct range 30.9 to 37.4, median Ct 34.1) whereas AML with inv(16) had a distinct signature characterized by higher HOXB3 expression (Ct range 26.4 to 30.1, median Ct 28.0). In addition, we have identified a subset of patients with intermediate cytogenetics who have high white cell counts, low HOXB3 expression and an inferior response to treatment. Therefore, in AML, the measurement of expression levels of only two HOX genes, HOXA5 and HOXB3 , complements cytogenetic analysis and may improve the yield of favorable gene rearrangements detected and provide additional prognostic information for cases with intermediate or failed cytogenetics.

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Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.98.3.1124 ◽

2001 ◽

Vol 98 (3) ◽

pp. 1124-1129 ◽

Cited By ~ 189

Author(s):

K. Virtaneva ◽

F. A. Wright ◽

S. M. Tanner ◽

B. Yuan ◽

W. J. Lemon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Myeloid Leukemia ◽

Trisomy 8 ◽

Normal Cytogenetics ◽

Biological Differences ◽

Acute Myeloid

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Differentiated Expression of microRNAs May be Regulated By the Vascular Endothelial Growth Factor in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.5322.5322 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5322-5322

Author(s):

Xiujin Ye ◽

Lixia Zhu

Keyword(s):

Vascular Endothelial Growth Factor ◽

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Myeloid Leukemia ◽

Lentiviral Vector ◽

Expression Level ◽

Vascular Endothelial ◽

High Group ◽

Endothelial Growth Factor ◽

Acute Myeloid

Abstract Background: Overexpression of the vascular endothelial growth factor (VEGF) is characterized in acute myeloid leukemia (AML), which stimulates endothelial cell mitogenesis and cell migration. MicroRNAs play a crucial role in the initiation and progression of malignancies. This study aimed to find the differential expression profiling of microRNAs that related with the expression level of VEGF in AML, and further explore the mechanism of VEGF in the course of AML. Methods: The overexpression of VEGFa lentiviral vector LV-VEGFa-O or the knockdown of VEGFa lentiviral vector LV-VEGFa-shRNA or the empty lentiviral vector LV-NC was transfected into AML cells HL60 and U937. MicroRNAs was analysed by using a commercial microarray platform (miRCURY LNA™ v.18.0, Exiqon) for microRNAs. A set of selected microRNAs and VEGF mRNA were further analyzed by using quantitative real-time PCR in 45 bone marrow (BM) from primary AML patients. Results: We have successfully constructed AML cell lines stably overexpressing VEGFa or knockdown VEGFa. Overexpression of VEGFa followed by a few changes of microRNAs profiling, that has-miR-1273f and has-miR-4679 were up-regulated, while eb-miR-BART10-3p and has-miR-3925-3p were down-regulated. However, knockdown of VEGFa significantly affected the expression profiling of microRNAs in AML cells. Thirty-three microRNAs were lower expression level than cells transfected with LV-NC (Figure 1). According to the expression level of VEGF, the AML patients were divided into two groups: VEGF-high group and VEGF-low group. We found five microRNAs (miR-20a, miR-93, miR-16-5p, miR-17 and miR-124-5p) were higher expression level in VEGF-high group than in VEGF-low group (p<0.05) (Figure 2). Conclusion: Five microRNAs (miR-20a, miR-93, miR-16-5p, miR-17 and miR-124-5p) were positively correlated with VEGFa in AML. It is necessary to further explore the role of the selected microRNAs in the signal pathways of the regulation of VEGFa in the course of AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Faculty Opinions recommendation of Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005129.60709 ◽

2002 ◽

Author(s):

Ulf Pettersson

Keyword(s):

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Myeloid Leukemia ◽

Trisomy 8 ◽

Normal Cytogenetics ◽

Biological Differences ◽

Acute Myeloid

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Abstract 3997: Expression profiling of a panel of apoptosis-associated microRNAs in acute myeloid leukemia identifies differentially expressed microRNAs that target epigenetic modifiers

10.1158/1538-7445.am2015-3997 ◽

2015 ◽

Author(s):

Eleftheria Hatzimichael ◽

Aggeliki Dasoula ◽

Maria Igglezou ◽

Andreas Katsenos ◽

Ioannis Sainis ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Myeloid Leukemia ◽

Differentially Expressed ◽

Epigenetic Modifiers ◽

Acute Myeloid

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MicroRNA Expression Profiles in Acute Myeloid Leukemia with Common Translocations.

Blood ◽

10.1182/blood.v110.11.3181.3181 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3181-3181

Author(s):

Zejuan Li ◽

Jun Lu ◽

Miao Sun ◽

Shuangli Mi ◽

Hao Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Myeloid Leukemia ◽

Target Genes ◽

Expression Profiles ◽

Genetic Alterations ◽

In Vivo Models ◽

Normal Controls ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. It is estimated that 13,410 cases will be diagnosed and 8,990 will die of AML in the United States in 2007 (http://seer.cancer.gov). AML is a genetically diverse hematopoietic malignancy with variable response to treatment. Expression profiling of protein-coding genes using DNA microarray in AML has resulted in inconsistent data from different laboratories. Therefore, further validation of these observations in large cohorts and in independent studies is definitely required before clinical application becomes feasible. Recently, Golub and colleagues described a new, bead-based flow cytometric microRNA (miRNAs, miRs) expression profiling method that could successfully classify tumors. MiRNAs are endogenous ∼22 nucleotide non-coding RNAs, which can function as oncogenes and tumor suppressors. To provide new insights into the complex genetic alterations in leukemogenesis and to identify novel markers for diagnosis and treatment of AML, we performed a genome-wide analysis of miRNA expression profiles using the bead-based method on 54 AML samples with common translocations including t(15;17), t(8;21), inv(16), and 11q23 rearrangement, along with normal controls. In both unsupervised and supervised hierarchical cluster analyses, we observed that t(15;17) samples grouped together as one cluster, as do the 11q23 rearrangement samples. Interestingly, t(8;21) and inv(16), both CBF (core-binding factor) AMLs, grouped together as a unique cluster. Forty-one miRNAs exhibited significantly differential expression between different subtypes of AMLs, and/or between AMLs and normal controls. Notably, expression signature of a minimal number of two, three, and seven miRNAs could be used for class prediction of CBF, t(15;17), and 11q23 rearrangement AMLs, respectively, with an overall diagnostic accuracy of 94–96%. We further showed that overexpression of the two discriminatory miRNAs in CBF AML is associated with epigenetic regulation, rather than DNA copy number amplification. Moreover, several important target genes of these discriminatory miRNAs have also been validated. We are currently exploring the role of these discriminatory miRNAs and their critical target genes in the development of AML using in vitro and in vivo models. This work will enhance our understanding of the biological role of these miRNAs and their targets in leukemogenesis.

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