Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells.

The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-β1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ(-/-) and old HSCs are more sensitive to TGF-β signaling. Importantly, we identified two populations of HSCs specifical…

MYST3/NCOA2-Induced Acute Myeloid Leukemia in Transgenic Fish

Abstract The MYST3/NCOA2 (MOZ/TIF2) fusion gene generated by the inv(8)(p11q13) chromosomal abnormality was described in a specific subgroup of acute myeloid leukemias (AML) that represents less than 5% of AML4/5. This abnormality fuses MYST3 (MOZ), a member of the MYST family of histone acetyl-transferases (HAT) to NCOA2 (TIF2), a member of the p160 HAT family. The transforming properties of MYST3/NCOA2 were demonstrated in mouse committed myeloid progenitors in vitro and in vivo. Hematopoiesis is very similar in zebrafish and in higher vertebrates. Homologues of a large number of genes involved in mammalian myelopoiesis were identified in this animal model. We have recently shown that nco…

TIF1γ : un gène suppresseur de tumeur dans la leucémie myélomonocytaire chronique

Colony-stimulating factor-1-induced oscillations in phosphatidylinositol-3 kinase/AKT are required for caspase activation in monocytes undergoing differentiation into macrophages.

Abstract The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasi…

A role for miR-142-3p in colony-stimulating factor 1-induced monocyte differentiation into macrophages

AbstractThe differentiation of human peripheral blood monocytes into macrophages can be reproduced ex vivo by culturing the cells in the presence of colony-stimulating factor 1 (CSF1). Using microarray profiling to explore the role of microRNAs (miRNAs), we identified a dramatic decrease in the expression of the hematopoietic specific miR-142-3p. Up- and down-regulation of this miRNA in primary human monocytes altered CSF1-induced differentiation of monocytes, as demonstrated by changes in the expression of the cell surface markers CD16 and CD163. One of the genes whose expression is repressed by miR-142-3p encodes the transcription factor Early Growth Response 2 (Egr2). In turn, Egr2 assoc…

A role for the transcription intermediary factor 2 in zebrafish myelopoiesis.

Objective TIF2 is fused with MOZ in the inv(8)(p11q13) acute myeloid leukemia. TIF2, member of the p160 family, is a histone acetyl transferase (HAT). Deletion of p160 genes were performed in mice. Some observations suggest that p160 family members may perform overlapping functions in mice. Therefore, we decided to choose the zebrafish model to study TIF2. The aim of this study was to characterize the role of this HAT during embryonic development. Material and Methods We use antisense, morpholino-modified oligomers to transiently knockdown tif2 gene, thus determining whether TIF2 plays a role in zebrafish early development. Results We show that tif2 is involved in embryogenesis and in primi…

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP- or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34+ cells. These chromatin-modifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential fo…

Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia.

Transcription intermediary factor 1γ (TIF1γ) was suggested to play a role in erythropoiesis. However, how TIF1γ regulates the development of different blood cell lineages and whether TIF1γ is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1γ was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1γ was almost undetectable in leukemic ce…

Cohen syndrome is associated with major glycosylation defects

International audience; Cohen syndrome (CS) is a rare autosomal recessive disorder with multisytemic clinical features due to mutations in the VPS13B gene, which has recently been described encoding a mandatory membrane protein involved in Golgi integrity. As the Golgi complex is the place where glycosylation of newly synthesized proteins occurs, we hypothesized that VPS13B deficiency, responsible of Golgi apparatus disturbance, could lead to glycosylation defects and/or mysfunction of this organelle, and thus be a cause of the main clinical manifestations of CS. The glycosylation status of CS serum proteins showed a very unusual pattern of glycosylation characterized by a significant accum…

Identification of novel, clonally stable, somatic mutations targeting transcription factors PAX5 and NKX2-3, the epigenetic regulator LRIF1, and BRAF in a case of atypical B-cell chronic lymphocytic leukemia harboring a t(14;18)(q32;q21)

Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) is usually straightforward, involving clinical, immunophenotypic (Matutes score), and (immuno)genetic analyses (to refine patient prognosis for treatment). CLL cases with atypical presentation (e.g., Matutes ≤ 3) are also encountered, and for these diseases, biology and prognostic impact are less clear. Here we report the genomic characterization of a case of atypical B-CLL in a 70-yr-old male patient; B-CLL cells showed a Matutes score of 3, chromosomal translocation t(14;18)(q32;q21) (BCL2/IGH), mutated IGHV, deletion 17p, and mutations in BCL2, NOTCH1 (subclonal), and TP53 (subclonal). Quite strikingly, a novel PAX5 mutation that w…

The Histone Acetyl-Transferase MOZ Cooperates with the Histone Methyl-Transferase MLL to Regulate HOX Gene Expression in Human Hematopoietic Stem Cells

Abstract MOZ (MOnocytic leukaemia Zinc finger protein) (also called MYST3 or KAT6A) is a member of the MYST family of HATs which likely acetylate H4K16. The MLL (MixedLineageLeukemia) gene is a frequent target for recurrent chromosomal translocations found in AML and ALL. MLL (KMT2A) is a methyl-transferase targeting H3K4. It was shown that MOZ/CBP leukemia, as observed in MLL-rearranged leukemias, harbors abnormal levels of homeobox (HOX) genes expression. HOX transcription factors have a crucial function in hematopoiesis regulation. In addition, HOXA5, HOXA7, and HOXA9 are often considered to be pivotal HOX genes for MLL transformation, constituting downstream targets of MLL. In our study…

Cellular Inhibitor of Apoptosis Protein-1 (cIAP1) Can Regulate E2F1 Transcription Factor-mediated Control of Cyclin Transcription

International audience; The inhibitor of apoptosis protein cIAP1 (cellular inhibitor of apoptosis protein-1) is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-B signaling pathways in the cytoplasm. However, in some primary cells and tumor cell lines, cIAP1 is expressed in the nucleus, and its nuclear function remains poorly understood. Here, we show that the N-terminal part of cIAP1 directly interacts with the DNA binding domain of the E2F1 transcription factor. cIAP1 dramatically increases the transcriptional activity of E2F1 on synthetic and CCNE promoters. This function is not conserved for cIAP2 and XIAP, which are cytoplasmic proteins. Chromatin immunoprec…

MiR-142-3p et leucémogenèse

Tif1gamma Is Essential for Macrophage Differentiation

Abstract Abstract 2370 TIF1gamma (or TRIM33) is an ubiquitous nuclear protein that belongs to the transcriptional intermediary factor 1 family. Human and mouse TIF1gamma are closely related to zebrafish moonshine (mon), a gene whose mutations disrupt embryonic and adult hematopoiesis with severe red blood cell aplasia. Targeted deletion of Tif1gamma is embryonic lethal in mice. In zebrafish and human CD34+ cells, TIF1gamma functionally links positive elongation factors such as p-TEFb and FACT to blood specific transcription complexes (e.g. the SCL/TAL1 complex) to regulate elongation of genes by antagonizing Pol II pausing. TIF1gamma also affects the human hematopoietic progenitor cell resp…

Symplekin, a polyadenylation factor, prevents MOZ and MLL activity on HOXA9 in hematopoietic cells

International audience; MOZ and MLL encoding a histone acetyltransferase and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. We have previously shown that MOZ and MLL cooperate to activate HOXA9 gene expression in hematopoietic stem/progenitors cells. To dissect the mechanism of action of this complex, we decided to identify new proteins interacting with MOZ. We found that the scaffold protein Symplekin that supports the assembly of polyadenylation machinery was identified by mass spectrometry. Symplekin interacts and co-localizes with both MOZ and MLL in immature hematopoietic cells. Its …

A MiR-142-3p/EGR2 Feedback Circuitry In Human CSF-1 Driven Differentiation of Monocytes Into Macrophages

Abstract Abstract 2366 Colony-stimulating factor-1 (CSF-1 or M-CSF) triggers the differentiation of human peripheral blood monocytes into macrophages through and integrated cytokine/transcription factors circuitry. Using microarray profiling to explore the role of microRNAs (miRNAs) in this molecular circuitry, we identified the down-regulation of miR-142-3p in human macrophages obtained from CSF-1-treated monocytes. We show that miR-142-3p is a repressor of the transcription factor EGR2 (Early Growth Response 2) through direct 3'UTR interactions. Interestingly, EGR2 binds the promoter of the pre-miR-142-3p gene to negatively regulate its expression, identifying a self-regulatory feedback l…

MOZ/TIF2-induced acute myeloid leukaemia in transgenic fish.

The inv(8)(p11q13) chromosomal abnormality, described in acute myeloid leukaemias (AML), fuses the histone acetyl-transferase (HAT) MYST3 (MOZ) gene with another HAT gene, NCOA2 (TIF2). We generated a transgenic zebrafish in which the MYST3/NCOA2 fusion gene was expressed under control of the spi1 promoter. An AML developed in 2 of 180 MYST3/NCOA2-EGFP-expressing embryos, 14 and 26 months after injection of the fusion gene in a one-cell embryo, respectively. This leukaemia was characterised by an extensive invasion of kidneys by myeloid blast cells. This model, which is the first zebrafish model of AML, demonstrates the oncogenic potency of MYST3/NCOA2 fusion gene.

Meeting Report: The 11th International Conference on Differentiation Therapy and Innovative Therapeutics in Oncology

The International Conference on Differentiation Therapy group of clinicians and researchers has met for more than 20 years and the most recent meeting in 2005 was held in Shanghai, China ( [1][1]). This group fostered the required networks to translate these novel strategies to clinical practice, as

Un nouveau modèle murin du vieillissement de l’hématopoïèse

Un nouveau modele murin du vieillissement de l’hematopoiese Ronan Quere 1,2, Jean-Noel Bastie1,2,3, Laurent Delva1,2 1 Inserm, UMR 866, faculte de medecine, universite de Bourgogne, 7 boulevard Jeanne d’Arc, 21000 Dijon, France ; 2 Labex LipSTIC, universite de Bourgogne, 21000 Dijon, France ; 3 hopital universitaire, service d’hematologie clinique, 21000 Dijon, France. ronan.quere@inserm.fr laurent.delva@u-bourgogne.fr