Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models

Kato, Naoko; Kitaura, Jiro; Doki, Noriko; Komeno, Yukiko; Watanabe‐Okochi, Naoko; Togami, Katsuhiro; Nakahara, Fumio; Oki, Toshihiko; Enomoto, Yutaka; Fukuchi, Yumi; Nakajima, Hitoshi; Harada, Yuka; Harada, Hironori; Kitamura, Toshio

doi:10.1182/blood-2010-02-270181

Cited by 57 publications

(66 citation statements)

References 54 publications

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“…21,22 In addition, recent work using retroviral overexpression demonstrated that a C-terminal Cebpa mutation (C/EBPa-C m ) was sufficient to cause AML and that FLT3 ITD could shorten the latency of AML induced by C/EBPa-C m . 23 To elucidate this discrepancy, we also monitored hematopoietic chimeras with single, either N-terminal (L allele) or C-terminal…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, it highlights the artificial effect of insertional mutagenesis in leukemogenesis in other mouse models, because we could not observe development of AML in mice expressing monoallelic C/EBPa and FLT3 ITD mutations within a time period that was sufficient to generate AML using retroviral expression of these lesions. 23 Our murine AML model mimics the human disease in many aspects as shown by morphology and phenotype. Interestingly, in contrast to the human disease, expression of FLT3 ITD in Cebpa mutant mice developing AML was not accompanied by higher white blood cell counts (Figure 1c).…”

Section: Discussionmentioning

confidence: 99%

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Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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“…Flow cytometric analysis was performed as described. 21,22 Morphological analysis Cytospin preparations of bone marrow (BM) cells or peripheral blood were stained with Giemsa. Images were obtained with a BX51 microscope and DP21 camera (Olympus, Tokyo, Japan).…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

Eμ/miR-125b transgenic mice develop lethal B-cell malignancies

et al. 2011

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MicroRNA-125b-1 (miR-125b-1) is a target of a chromosomal translocation t(11;14)(q24;q32) recurrently found in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation results in overexpression of miR-125b controlled by immunoglobulin heavy chain gene (IGH) regulatory elements. In addition, we found that six out of twenty-one BCP-ALL patients without t(11;14)(q24;q32) showed overexpression of miR-125b. Interestingly, four out of nine patients with BCR/ABL-positive BCP-ALL and one patient with B-cell lymphoid crisis that had progressed from chronic myelogenous leukemia overexpressed miR-125b. To examine the role of the deregulated expression of miR-125b in the development of B-cell tumor in vivo, we generated transgenic mice mimicking the t(11;14)(q24;q32) (El/miR-125b-TG mice). El/miR-125b-TG mice overexpressed miR-125b driven by IGH enhancer and promoter and developed IgM-negative or IgM-positive lethal B-cell malignancies with clonal proliferation. B cells obtained from the El/miR-125b-TG mice were resistant to apoptosis induced by serum starvation. We identified Trp53inp1, a proapoptotic gene induced by cell stress, as a novel target gene of miR-125b in hematopoietic cells in vitro and in vivo. Our results provide direct evidence that miR-125b has important roles in the tumorigenesis of precursor B cells.

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“…CEBPA is a gene that plays a role to induce the differentiation of myeloid cells [9,16,[24][25][26]. Based on previous in vitro and in vivo studies, CEBPA expression could be inhibited by BCR-ABL through MAPK-hnRNP-E2 pathway in CML blast crisis [9].…”

Section: Discussionmentioning

confidence: 99%

HES-1 and CEBPA mRNA in Chronic and Late Phase (accelerated and blast crisis) of Chronic Myeloid Leukemia (CML) Patients

Rahmawati¹,

Fatmawati²,

Purwanto³

et al. 2017

J Leuk

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Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder of hematopoietic , characterized by Philadelphia chromosome containing BCR-ABL fusion gene. The gene encodes protein with constitutive tyrosine kinase activity result in myeloid proliferation and leads to form an early phase of CML called chronic phase. Unsuccessful treatment will lead to progression of the disease into late phase (accelerated and blast crisis). The mechanisms involving disease progression are still poorly understood. It is assumed that additional genetic event involves in differentiation blocking of myeloid progenitor cells, such as Hes-1 overexpression and CEBPA down regulation. However, study on the expression of these genes in CML patient's samples is still limited. This study aims to measure Hes-1 and CEBPA mRNA in chronic and late phase of CML patients. The peripheral blood mRNA level of Hes-1 was measured in CML patient's sample with BCR-ABL positive both in chronic phase (n=61) and late phase (n=17) using qRT-PCR with GAPDH as internal control. Hes-1 mRNA was statistically higher (p value=0.0) in the chronic phase (mean ± SD=97.8 ± 236.6) compared to those in late phase (mean ± SD=8.5 ± 30.7). In addition, even though CEBPA expression in chronic and late phase were not statistically different (p value=0.1), those in chronic phase (mean ± SD=5.2 ± 16.0) were generally higher compared to those in late phase (mean ± SD=1.7 ± 2.4). Hes-1 expression upregulated in 70.5% of chronic phase patients and in 17.6% of late phase patients, whereas CEBPA expression down regulated in 42.6% of chronic phase patients and in 47.1% in late phase patients. High standard deviation, particularly in mRNA Hes-1 gene expression measurement of the chronic phase, indicated the presence of individual variations in the sample that might be influenced by other genetic factors. This study found that Hes-1 mRNA is significantly higher in peripheral blood of chronic phase than blast crisis CML, whereas CEBPA mRNA is not different.

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Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models

Cited by 57 publications

References 54 publications

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Eμ/miR-125b transgenic mice develop lethal B-cell malignancies

HES-1 and CEBPA mRNA in Chronic and Late Phase (accelerated and blast crisis) of Chronic Myeloid Leukemia (CML) Patients

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