Distinct gene expression pattern of RUNX1 mutations coordinated by target repression and promoter hypermethylation in acute myeloid leukemia

Purpose The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2mut in a large cohort of patients with AML in the context of other AML-associated aberrations. Patients and Methods Samples from 783 younger adult patients with AML were analyzed for the presence of TET2mut (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome. Results In total, 66 TET2mut were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (P < .001). TET2mut were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2mut-associated biology. TET2mut did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2mut and/or IDHmut revealed shorter overall survival (P = .03), although this association was not independent from known risk factors. Conclusion TET2mut were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDHmut, which supported recent data on a common mechanism of action that might obscure the impact of TET2mut if compared against all other patients with AML.

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Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia

Leukemia ◽

10.1038/leu.2011.134 ◽

2011 ◽

Vol 25 (10) ◽

pp. 1649-1652 ◽

Cited By ~ 40

Author(s):

N Konstandin ◽

S Bultmann ◽

A Szwagierczak ◽

A Dufour ◽

B Ksienzyk ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Expression Pattern ◽

Myeloid Leukemia ◽

Gene Expression Pattern ◽

Global Gene Expression ◽

Global Gene Expression Pattern ◽

Secondary Acute Myeloid Leukemia ◽

Acute Myeloid

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Characterization of NPM1-Mutated/FLT3 ITD-Negative Acute Myeloid Leukemia with Normal Karyotype by Gene Expression Profiling.

Blood ◽

10.1182/blood.v108.11.155.155 ◽

2006 ◽

Vol 108 (11) ◽

pp. 155-155 ◽

Cited By ~ 1

Author(s):

Lars Bullinger ◽

Konstanze Dohner ◽

Raphael Kranz ◽

Frank G. Rucker ◽

Stefan Frohling ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Expression Pattern ◽

Myeloid Leukemia ◽

Gene Expression Pattern ◽

Normal Karyotype ◽

Molecular Profile ◽

Data Set ◽

Mutational Status ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) with normal karyotype comprises a large number of molecularly distinct variants. For example the presence of internal tandem duplications (ITDs) of the FLT3 (fms-related tyrosine kinase 3) gene is associated with poor outcome, whereas mutations of the NPM1 (nucleophosmin) gene are prognostically favorable. However, this effect is mainly attributed to the NPM1-mutated/FLT3 ITD-negative AML cases. While NPM1-mutated cases are characterized by a distinct gene expression pattern, it remains unclear whether NPM1-mutated/FLT3 ITD-negative cases also display a characteristic signature, which might provide additional insights into the molecular basis for the good clinical outcome. Thus, we sought to identify a molecular profile for AML cases with NPM1-mutated/FLT3 ITD-negative normal karyotype disease. Towards this goal, we profiled gene expression of 138 samples of adult AML patients with normal karyotype using DNA microarray technology. All samples analyzed were derived from AML patients entered within the randomized multicenter treatment trial HD-98A of the German-Austrian AML Study Group (AMLSG). Based on supervised data analyses we were able to identify a 116-genes comprising expression pattern correlated with NPM1-mutated and FLT3 ITD-negative AML cases. In accordance with previous findings in NPM1-mutated cases (Alcalay et al. 2005, Verhaak et al. 2005), the NPM1-mutated/FLT3 ITD-negative pattern was also in part characterized by a prominent HOX gene cluster, which clearly separated the NPM1-wildtype from the NPM1-mutated cases. Similarly, the expression levels of BAALC and MN1 were correlated with the NPM1 mutational status, with NPM1-unmutated cases displaying higher BAALC and MN1 expression in our data set. However, as expected the newly defined signature also defined a NPM1-mutated group that did not contain many FLT3 ITD-positive samples. This group was characterized by several interesting genes including for example TLE1, which encodes a Groucho/TLE family protein. Groucho/TLE family proteins are transcriptional co-repressors, which mediate repression essential in embryonic development and are involved in regulation of Wnt signaling in adult tissue. Moreover, we identified several other genes of potential pathogenic relevance which also have been previously shown to be predictive in normal karyotype AML. Our findings support a distinct molecular mechanism associated with the favorable outcome of NPM1-mutated/FLT3 ITD-negative AML cases. Furthermore, the reported signature might contribute to improved risk stratification and clinical management of AML patients with normal karyotype disease.

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NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern

Blood ◽

10.1182/blood-2011-04-346643 ◽

2011 ◽

Vol 118 (13) ◽

pp. 3645-3656 ◽

Cited By ~ 152

Author(s):

Iris H. I. M. Hollink ◽

Marry M. van den Heuvel-Eibrink ◽

Susan T. C. J. M. Arentsen-Peters ◽

Marta Pratcorona ◽

Saman Abbas ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Expression Pattern ◽

Myeloid Leukemia ◽

Gene Expression Pattern ◽

Chromosome 11P15 ◽

Hox Gene ◽

Cell Counts ◽

Dismal Prognosis ◽

Acute Myeloid

Abstract Translocations involving nucleoporin 98kD (NUP98) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML) but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically normal (CN)–AML cases. To determine their exact frequency, we screened > 1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1-specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1-positive AML cases had significantly higher white blood cell counts (median, 147 × 109/L), more frequent FAB-M4/M5 morphology (in 63%), and more CN-AML (in 78%), FLT3/internal tandem duplication (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1-negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was < 10% for both pediatric and adult NUP98/NSD1-positive AML patients. NUP98/NSD1-positive AML showed a characteristic HOX-gene expression pattern, distinct from, for example, MLL-rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed.

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MLL partner genes drive distinct gene expression profiles and genomic alterations in pediatric acute myeloid leukemia: an AIEOP study

Leukemia ◽

10.1038/leu.2010.316 ◽

2011 ◽

Vol 25 (3) ◽

pp. 560-563 ◽

Cited By ~ 13

Author(s):

M Pigazzi ◽

R Masetti ◽

S Bresolin ◽

A Beghin ◽

A Di Meglio ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Genomic Alterations ◽

Pediatric Acute Myeloid Leukemia ◽

Distinct Gene ◽

Acute Myeloid

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Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

Haematologica ◽

10.3324/haematol.2011.046888 ◽

2011 ◽

Vol 96 (12) ◽

pp. 1783-1791 ◽

Cited By ~ 27

Author(s):

A. C. Russ ◽

S. Sander ◽

S. C. Luck ◽

K. M. Lang ◽

M. Bauer ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Target Gene ◽

Pattern Analysis ◽

Gene Expression Pattern ◽

Gene Interactions ◽

Microrna Target ◽

Expression Pattern Analysis ◽

Acute Myeloid

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The expression pattern of erythrocyte/megakaryocyte-related transcription factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia

Blood ◽

10.1182/blood.v86.8.3173.bloodjournal8683173 ◽

1995 ◽

Vol 86 (8) ◽

pp. 3173-3180 ◽

Cited By ~ 1

Author(s):

T Shimamoto ◽

K Ohyashiki ◽

JH Ohyashiki ◽

K Kawakubo ◽

T Fujimura ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Transcription Factors ◽

Expression Pattern ◽

Cell Lines ◽

Myeloid Leukemia ◽

Cell Leukemia ◽

Stem Cell Leukemia ◽

Acute Myeloid

To understand the clinical implications of transcription factors and their biologic roles during cellular differentiation in the hematopoietic system, we examined the expression of GATA-1, GATA-2, and stem cell leukemia (SCL) gene in human leukemia cell lines and various leukemia patients using the reverse transcriptase-polymerase chain reaction. Cell lines exhibiting megakaryocytic or erythrocytic phenotypes had GATA-1, GATA-2, and SCL gene transcripts, while monocytic cell lines had no detectable GATA-1, GATA-2, or SCL gene mRNA. In some myeloid cell lines, GATA-1 expression, but not SCL gene expression, was detected; GATA-1 expression in HL-60 cells was downregulated during the process of monocytic differentiation. We next examined GATA-1, GATA-2, and SCL gene expression in 110 leukemia samples obtained from 76 patients with acute myeloid leukemia (AML), 19 with acute lymphoblastic leukemia (ALL), and 15 with chronic myeloid leukemia in blast crisis (CML-BC). SCL gene expression was usually accompanied by GATA-1 expression and was preferentially detected in patients with leukemia exhibiting megakaryocytic or erythrocytic phenotypes, while patients with monocytic leukemia were clustered in the group with no detectable GATA-1 expression. None of the patients with ALL or CML-lymphoid-BC expressed SCL. De novo AML patients with SCL gene expression had a lower complete remission (CR) rate and had a significantly poorer prognosis. Among the patients with AML not expressing SCL, a high percentage of patients with CD7+ AML and CD19+ AML had detectable GATA-1, while patients with GATA-1-negative AML had the best CR rate (87.5%). Our results suggest that the expression pattern of transcription factors reflects the lineage potential of leukemia cells, and GATA-1 and SCL gene expression may have prognostic value for the outcome of patients with AML.

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RUNX1 Mutations in Acute Myeloid Leukemia: Results From a Comprehensive Genetic and Clinical Analysis From the AML Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2010.30.7926 ◽

2011 ◽

Vol 29 (10) ◽

pp. 1364-1372 ◽

Cited By ~ 188

Author(s):

Verena I. Gaidzik ◽

Lars Bullinger ◽

Richard F. Schlenk ◽

Andreas S. Zimmermann ◽

Jürgen Röck ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Multivariable Analysis ◽

Gene Expression Pattern ◽

Clinical Analysis ◽

Microarray Gene Expression ◽

Hematopoietic Stem ◽

Free Survival ◽

Acute Myeloid

Purpose To evaluate frequency, biologic features, and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). Patients and Methods Diagnostic samples from 945 patients (age 18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n = 269), microarray gene expression analysis was performed. Results Fifty-nine RUNX1 mutations were identified in 53 (5.6%) of 945 cases, predominantly in exons 3 (n = 11), 4 (n = 10), and 8 (n = 23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46 of 640, 7.2%; cytogenetically normal, 34 of 538, 6.3%), whereas they were less frequent in adverse-risk cytogenetics (five of 109, 4.6%) and absent in core-binding-factor AML (0 of 77) and acute promyelocytic leukemia (0 of 61). RUNX1 mutations were associated with MLL-partial tandem duplications (P = .0007) and IDH1/IDH2 mutations (P = .03), inversely correlated with NPM1 (P < .0001), and in trend with CEBPA (P = .10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3), or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, P = .047, for RUNX1-mutated and wild-type patients, respectively), as well as inferior event-free survival (EFS; P < .0001), relapse-free survival (RFS, P = .022), and overall survival (P = .051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (P = .007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem-cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (P < .0001). Conclusion AML with RUNX1 mutations are characterized by distinct genetic properties and are associated with resistance to therapy and inferior outcome.

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The expression pattern of erythrocyte/megakaryocyte-related transcription factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia

Blood ◽

10.1182/blood.v86.8.3173.3173 ◽

1995 ◽

Vol 86 (8) ◽

pp. 3173-3180 ◽

Cited By ~ 53

Author(s):

T Shimamoto ◽

K Ohyashiki ◽

JH Ohyashiki ◽

K Kawakubo ◽

T Fujimura ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Transcription Factors ◽

Expression Pattern ◽

Cell Lines ◽

Myeloid Leukemia ◽

Cell Leukemia ◽

Stem Cell Leukemia ◽

Acute Myeloid

Abstract To understand the clinical implications of transcription factors and their biologic roles during cellular differentiation in the hematopoietic system, we examined the expression of GATA-1, GATA-2, and stem cell leukemia (SCL) gene in human leukemia cell lines and various leukemia patients using the reverse transcriptase-polymerase chain reaction. Cell lines exhibiting megakaryocytic or erythrocytic phenotypes had GATA-1, GATA-2, and SCL gene transcripts, while monocytic cell lines had no detectable GATA-1, GATA-2, or SCL gene mRNA. In some myeloid cell lines, GATA-1 expression, but not SCL gene expression, was detected; GATA-1 expression in HL-60 cells was downregulated during the process of monocytic differentiation. We next examined GATA-1, GATA-2, and SCL gene expression in 110 leukemia samples obtained from 76 patients with acute myeloid leukemia (AML), 19 with acute lymphoblastic leukemia (ALL), and 15 with chronic myeloid leukemia in blast crisis (CML-BC). SCL gene expression was usually accompanied by GATA-1 expression and was preferentially detected in patients with leukemia exhibiting megakaryocytic or erythrocytic phenotypes, while patients with monocytic leukemia were clustered in the group with no detectable GATA-1 expression. None of the patients with ALL or CML-lymphoid-BC expressed SCL. De novo AML patients with SCL gene expression had a lower complete remission (CR) rate and had a significantly poorer prognosis. Among the patients with AML not expressing SCL, a high percentage of patients with CD7+ AML and CD19+ AML had detectable GATA-1, while patients with GATA-1-negative AML had the best CR rate (87.5%). Our results suggest that the expression pattern of transcription factors reflects the lineage potential of leukemia cells, and GATA-1 and SCL gene expression may have prognostic value for the outcome of patients with AML.

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