The N-terminal CEBPA mutant in acute myeloid leukemia impairs CXCR4 expression

Kuo, Yueh‐Hsiung; Hou, Hsin An; Chen, Yin Kai; Li, Li Yu; Chen, Po Hsuen; Tseng, Mei‐Hui; Huang, Chi Fei; Lee, Fen Yu; Liu, Ming Chih; Liu, Chia Wen; Chou, Wen‐Chien; Liu, Chieh‐Yu; Tang, Jih-Luh; Yao, Ming; Tien, Hwei‐Fang

doi:10.3324/haematol.2014.107821

Cited by 12 publications

(12 citation statements)

References 45 publications

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“…P30 is initiated at an in-frame AUG codon downstream of CEBPA mRNA, and thus lacks the first transactivation domains (TAD) at the N-terminus ( 26 , 27 ). Dominant negative C/EBPα P30 isoform loses ability to regulate many differentiation associated and antitumor genes but preserved growth arresting ability in AML cells ( 25 , 28 ). Moreover, P30 also has target genes distinct from P42, such as PIN1, microRNA-181a and long non-coding RNA UCA1 encoding genes ( 29 – 31 ).…”

Section: Introductionmentioning

confidence: 99%

Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells

Wang

Xiao

Zhang

et al. 2015

International Journal of Oncology

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All-trans retinoic acid (ATRA) is one of the first line agents in differentiation therapy for acute promyelocytic leukemia (APL). However, drug resistance is a major problem influencing the efficacy of ATRA. Identification of mechanisms of ATRA resistance are urgenly needed. In the present study, we found that expression of C/EBPα, an important transcription factor for myeloid differentiation, was significantly suppressed in ATRA resistant APL cell line NB4-R1 compared with ATRA sensitive NB4 cells. Moreover, two forms of C/EBPα were unequally suppressed in NB4-R1 cells. Suppression of the full-length form P42 was more pronounced than the truncated form P30. Inhibition of PI3K/Akt/mTOR pathway was also observed in NB4-R1 cells. Moreover, C/EBPα expression was reduced by PI3K inhibitor LY294002 and mTOR inhibitor RAD001 in NB4 cells, suggesting that inactivation of the PI3K/Akt/mTOR pathway was responsible for C/EBPα suppression in APL cells. We restored C/EBPα P42 and P30 by lentivirus vectors in NB4-R1 cells, respectively, and found C/EBPα P42, but not P30, could increase CD11b, CD14, G-CSFR and GM-CSFR expression, which indicated the occurrence of myeloid differentiation. Further upregulating of CD11b expression and differential morphological changes were found in NB4-R1 cells with restored C/EBPα P42 after ATRA treatment. However, CD11b expression and differential morphological changes could not be induced by ATRA in NB4-R1 cells infected with P30 expressing or control vector. Thus, we inferred that ATRA sensitivity of NB4-R1 cells was enhanced by restoration of C/EBPα P42. In addition, we used histone deacetylase inhibitor trichostatin (TSA) to restore C/EBPα expression in NB4-R1 cells. Similar enhancement of myeloid differentiation and cell growth arrest were detected. Together, the present study demonstrated that suppression of C/EBPα P42 induced by PI3K/Akt/mTOR inhibition impaired the differentiation and ATRA sensitivity of APL cells. Restoring C/EBPα P42 is an attractive approach for differentiation therapy in ATRA resistant APL.

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Section: Introductionmentioning

confidence: 99%

Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells

Wang

Xiao

Zhang

et al. 2015

International Journal of Oncology

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“…CEBPα, one of the key transcription factors deregulated in AML [88], regulates cellular adhesion via the stem cell homing receptor CXCR4 [89]. CXCR4 is an alpha-chemokine receptor specific for SDF1α, a chemokine important for HSC homing to the bone marrow, retention of HSCs in the bone marrow, and HSC quiescence.…”

Section: Oncogenes Directly Deregulate Cellular Adhesionmentioning

confidence: 99%

Oncogenic Deregulation of Cell Adhesion Molecules in Leukemia

Windisch¹,

Pirschtat²,

Kellner³

et al. 2019

Cancers

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Numerous cell–cell and cell–matrix interactions within the bone marrow microenvironment enable the controlled lifelong self-renewal and progeny of hematopoietic stem and progenitor cells (HSPCs). On the cellular level, this highly mutual interaction is granted by cell adhesion molecules (CAMs) integrating differentiation, proliferation, and pro-survival signals from the surrounding microenvironment to the inner cell. However, cell–cell and cell–matrix interactions are also critically involved during malignant transformation of hematopoietic stem/progenitor cells. It has become increasingly apparent that leukemia-associated gene products, such as activated tyrosine kinases and fusion proteins resulting from chromosomal translocations, directly regulate the activation status of adhesion molecules, thereby directing the leukemic phenotype. These observations imply that interference with adhesion molecule function represents a promising treatment strategy to target pre-leukemic and leukemic lesions within the bone marrow niche. Focusing on myeloid leukemia, we provide a current overview of the mechanisms by which leukemogenic gene products hijack control of cellular adhesion to subsequently disturb normal hematopoiesis and promote leukemia development.

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“…In the process of doing so, it also appears to enhance recruitment of RNA polymerase II. Many other LncRNAs are regulated by NTCs in T-ALL cells (Durinck et al, 2014; Trimarchi et al, 2014), suggesting that NTC-regulated LncRNAs have a widespread role in regulating Notch target expression, particularly those that are controlled by Notch-sensitive long-range enhancers.…”

Section: Insights From Genome-wide Studies Of Notch Response Elementsmentioning

confidence: 99%

The Role of Notch Receptors in Transcriptional Regulation

Wang

Zang

Liu

et al. 2015

Journal Cellular Physiology

109

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Notch signaling has pleiotropic context-specific functions that have essential roles in many processes, including embryonic development and maintenance and homeostasis of adult tissues. Aberrant Notch signaling (both hyper- and hypoactive) is implicated in a number of human developmental disorders and many cancers. Notch receptor signaling is mediated by tightly regulated proteolytic cleavages that lead to the assembly of a nuclear Notch transcription complex, which drives the expression of downstream target genes and thereby executes Notch’s functions. Thus, understanding regulation of gene expression by Notch is central to deciphering how Notch carries out its many activities. Here, we summarize the recent findings pertaining to the complex interplay between the Notch transcriptional complex and interacting factors involved in transcriptional regulation, including co-activators, cooperating transcription factors, and chromatin regulators, and discuss emerging data pertaining to the role of Notch-regulated noncoding RNAs in transcription.

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The N-terminal CEBPA mutant in acute myeloid leukemia impairs CXCR4 expression

Cited by 12 publications

References 45 publications

Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells

Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells

Oncogenic Deregulation of Cell Adhesion Molecules in Leukemia

The Role of Notch Receptors in Transcriptional Regulation

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