CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

Wang, Qian Fei; Friedman, Alan D.

doi:10.1182/blood.v99.8.2776

Cited by 79 publications

(78 citation statements)

References 62 publications

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“…Csf3r mRNA expression levels in RP7, RP11, and in five clones expressing RARα-PLZF fused to the tag for tandem affinity purification (RP-TAP15, 19,23,24,33) as well as RP-HA were less than 20% that of parental 32D cells by Northern blotting and/or quantitative RT-PCR analysis ( Fig. 1 D and E).…”

Section: Resultsmentioning

confidence: 99%

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Girard

Tremblay

Humbert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.APL | granulocyte differentiation | transcription inhibition | histone modification | protein interaction

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Section: Resultsmentioning

confidence: 99%

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Girard

Tremblay

Humbert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The difference in the role of C/EBPalpha between the adipocyte system and granulocyte system is not clear. Interestingly, C/EBPalpha is required for adipocyte differentiation, whereas in the granulocyte differentiation system C/EBPalpha can be replaced by C/EBPbeta (Popernack et al, 2001;Jones et al, 2002;Wang and Friedman 2002). However, only a low level of C/EBPalpha is sufficient for granulocyte differentiation.…”

Section: -------------------------------------mentioning

confidence: 99%

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

et al. 2006

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Fms interacting protein (FMIP) is a substrate for Fms tyrosine kinase, and a nuclear/cytoplasm shuttling protein with a leucine zipper. As the phosphorylation of FMIP is observed in insulin-stimulated preadipocytes, we examined the role of FMIP in adipocyte differentiation, using the mesenchymal multipotent stem cells, C2C12 cells, that can differentiate into adipocytes, muscle cells and osteoblasts. Ectopic expression of FMIP in C2C12 impairs the adipocyte differentiation induced by treatment with insulin, dexamethasone and 3-isobutyl-1-methylxanthine. These cells exhibit muscle phenotype with multinuclear morphology. Furthermore, knockdown of endogenous FMIP expression by small interfering RNA improves adipocytic lineage commitment of C2C12 cells, while impairing muscle differentiation. Upon stimulation with insulin, CCAAT/enhancer binding protein (C/EBP)-beta, but not C/EBPalpha, is upregulated in cells expressing ectopic FMIP, whereas in FMIP knockdown cells, C/EBPalpha is constitutively expressed. Ectopic expression of C/EBPalpha counteracts the effects of FMIP, whereas C/EBPalpha knockdown partially mimics the effects of FMIP in this system. Northern blot analysis and reverse transcriptase-polymerase chain reaction study reveal that ectopic FMIP-expressing cells do not contain the polyadenylated C/EBPalpha mRNA, but contain the C/EBPalpha pre-mRNA, suggesting that FMIP plays a role in RNA processing and/or export. Indeed, a member of the THO complex that plays a role in mRNA export, THOC1, is co-precipitated with FMIP. The data we have acquired on FMIP suggest that it is a target for tyrosine kinase receptors that potentiate mRNA export.

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“…However, in mutated cases with multiple alterations of CEBPA, preventing expression of wt protein, or in single alterations with expression of p30 dominant negative form, the persistence of CEBPA residual cellular functions has been demonstrated. 31,33,34 Therefore, those cases are not identical to KO models since the loss of transactivating properties is dependent of on cis-regulating elements of the CEBPA target genes. Moreover, other members of the CEBPA family, including CEBPB and CEBPE, could partially prevent the effects of the loss of function of mutated CEBPA and allow incomplete myeloid differentiation resulting in M1, M2, M4 and M5 blasts.…”

Section: Pathogenetic Role Of Cebpa Mutationsmentioning

confidence: 99%

“…It has previously been reported that biallelic mutations of another early myeloid differentiation gene (AML1/ RUNX1) could induce M0 AML subtype. 2 Furthermore, mice models of CML blast crisis with CEBPA knockout result in immature erythroid leukemia 30,31 and expression of a dominant negative 30-kDa CEBPA protein inhibits differentiation of myeloid and erythroid progenitors. 32 On the other hand, all CEBPAmutated patients reviewed in this work had M1, M2, M4 or M5 AML subtypes, clearly showing persistence of myeloid differentiation in blast cells.…”

Section: Pathogenetic Role Of Cebpa Mutationsmentioning

confidence: 99%

CEBPA point mutations in hematological malignancies

et al. 2005

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The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcription factor strongly implicated in myelopoiesis through control of proliferation and differentiation of myeloid progenitors. Recently, several works have reported the presence of CEBPA-acquired mutations in hematological malignancies. In this work, we analyzed characteristics of mutations and their correlation with disease characteristics described in previous studies. In the 1175 patients reported, 146 CEBPA mutations were identified in 96 patients. Mutations were found in the whole gene sequence, but cluster regions were clearly identified. Furthermore, two categories of mutations were reported: out-of-frame ins/del often in the N-terminal region, and in-frame ins/del often in the C-terminal region. CEBPA mutations were reported exclusively in acute myeloid leukemia (AML) (according to WHO classification criteria) and mutated patients preferentially belonged to M1, M2 and M4 FAB subtypes. All but one case belonged to the 'intermediate' prognostic subgroup of MRC classification. In the absence of poor prognostic factors, patients with CEBPA mutation had favorable outcome, very similar to that of the t(8;21), inv(16), t(15;17) subgroup. Systematic analysis of CEBPA mutations, in addition to that of alterations in master genes of hematopoiesis, may be useful to assess the prognosis of AML particularly in patients belonging to the 'intermediate' prognostic subgroup.

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CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

Cited by 79 publications

References 62 publications

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

CEBPA point mutations in hematological malignancies

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