Clinical outcome of <i>de novo</i> acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review

Baldus, Claudia D.; Mrózek, Krzysztof; Marcucci, Guido; Bloomfield, Clara D.

doi:10.1111/j.1365-2141.2007.06566.x

Cited by 90 publications

(69 citation statements)

References 84 publications

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“…Similarly, in normal karyotype AML, patients without FLT3-ITD, TK mutations or MLL-PTD represented almost 50% of AMLs and have a prognosis that is significantly more different than that of patients harboring these mutations. 19 Therefore, we think that our proteomic classification reflects the separation into two subgroups of approximately similar size but different prognostics. Further studies on the correlation between molecular status and proteomics could further improve this issue.…”

Section: Discussionmentioning

confidence: 94%

Expression of S100A8 in leukemic cells predicts poor survival in de novo AML patients

et al. 2010

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Section: Discussionmentioning

confidence: 94%

Expression of S100A8 in leukemic cells predicts poor survival in de novo AML patients

et al. 2010

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“…14 It has been demonstrated that NPM1 mutations are associated with specific gene expression signatures. 35,[55][56][57] These transcript signatures are characterized by overexpression of homeobox genes (HOXA, HOXB families and TALE genes). Interestingly, the microRNAs (-10a, -10b, -196a, -196b) that are up-regulated in AML with mutant NPM1, are all located within the genomic cluster of HOX genes.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia

Jongen‐Lavrencic

Sun

Dijkstra

et al. 2008

Blood

368

329

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IntroductionThe pathogenesis of acute myeloid leukemia (AML) is a heterogeneous multistep process affecting cell differentiation, proliferation, and apoptosis, which ultimately leads to malignant transformation of hematopoietic progenitors. Deregulated gene expression, disrupting cellular pathways, has been used for the classification of AML. [1][2][3][4][5] The prognosis of AML depends on well-defined leukemiaspecific prognostic factors, such as the cytogenetic abnormalities t(15;17), t(8;21), and inv(16) with a relatively favorable prognosis and the 3q26 abnormalities, Ϫ5/Ϫ5q and Ϫ7/Ϫ7q with an unfavorable prognosis. [6][7][8] Furthermore, various molecular abnormalities in AML with normal karyotype have apparent prognostic significance, such as the somatic gene mutations in nucleophosmin-1 (NPM1), FMS-like tyrosine kinase 3 (FLT3, internal tandem duplications [ITDs]), and CCAAT/enhancer binding protein alpha (CEBPA). 9-13 NPM1 mutations frequently occur in association with FLT3-ITD mutations. Several studies on the clinical impact in AML subgroups revealed that the subset of AML with NPM1 mutations lacking FLT3-ITD mutations has a significantly better overall survival. 14 MicroRNAs are a class of small noncoding RNAs that regulate translation of protein coding mRNAs and thereby protein expression, by translation inhibition or cleavage of the mRNA transcripts. 15 There is an accumulating body of evidence indicating that microRNAs play important roles in cellular growth and differentiation. 16 MicroRNA expression profiles of tumor samples have recently been shown to provide phenotypic signatures of particular cancer types. [17][18][19][20][21][22] MicroRNAs can act as tumor suppressor. For instance, expression of some microRNAs, such as let-7 23 and the microRNA15a/16-1 cluster, 24 has been reported to be reduced in lung cancer and chronic lymphocytic leukemia (CLL) respectively, suggesting tumor suppressor activities. In contrast, microRNA-17-92 cluster 25 and microRNA-155/BIC 26,27 have been shown to be overexpressed in B-cell lymphomas, indicative of their oncogenic potential.A characteristic microRNA expression signature may aid in the diagnosis of certain types or subtypes of cancers. It has been shown that microRNA profiles of bone marrow samples from patients with acute lymphoblastic leukemia (ALL) discriminated subsets of ALL with different molecular aberrancies. 17 In AML, information about microRNA expression has been gathered only in a limited series of patients so far. Debernardi et al 28 reported in 30 AML patients with normal cytogenetics that microRNA-181a correlates with cytologic subclass. They also reported that the expression of microRNA-10a, microRNA-10b, and microRNA-196a, which are located in intergenic regions in the HOX gene clusters, in AML correlates positively with HOXA and HOXB gene expression, suggesting a role of these microRNAs in aberrant regulation of proliferation and differentiation in leukemogenesis. 28 It was recently reported that microRNA expression signatures discriminate...

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“…The ETS transcription factor ERG is overexpressed in subtypes of newly diagnosed T-ALL and AML patients. Overexpression of ERG mRNA expression was further correlated with poor prognosis; however, the downstream effects of deregulated mRNA expression are not yet understood (Baldus et al, 2007). Interestingly, patients with complex cytogenetics attribute aberrant ERG expression to recurring chromosomal abnormalities such as amplification at regions of the ERG loci (Baldus et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

et al. 2011

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E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were coexpressed in 80% of AML (n ¼ 30) and 40% in T-ALL (n ¼ 30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were costimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.

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Clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review

Cited by 90 publications

References 84 publications

Expression of S100A8 in leukemic cells predicts poor survival in de novo AML patients

Expression of S100A8 in leukemic cells predicts poor survival in de novo AML patients

MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

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