The Role of Additional Sex Combs-Like Proteins in Cancer

Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. An epigenetic regulator, ASXL1 ca-nonically directs the deposition of H3K27me3 via the polycomb repressive complex 2. However, its precise role in myeloid lineage maturation is incompletely described. We utilized single cell RNA sequencing (scRNA-seq) on a murine model of hematopoietic-specific ASXL1 deletion and identified a specific role for ASXL1 in terminal granulo-cyte maturation. Terminal maturation is accompanied by down regulation of Myc ex-pression and cell cycle exit. ASXL1 deletion leads to hyperactivation of Myc in granu-locyte precursors and a quantitative decrease in neutrophil production. This failure of normal developmentally-associated Myc suppression is not accompanied by signifi-cant changes in the landscape of covalent histone modifications including H3K27me3. Examining the genome-wide localization of ASXL1 in myeloid progenitors revealed strong co-localization with RNA Polymerase II (RNAPII) at the promoters and spread across the gene bodies of transcriptionally active genes. ASXL1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription, consistent with the known role of ASXL1 as a mediator of RNAPII pause release. These results suggest that ASXL1 in-hibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator and highlighting a novel potential oncogenic mechanism for ASXL1 mutations in myeloid malignancies.

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Role of the additional sex combs-like (ASXL) proteins in mouse and human trophoblast differentiation

Placenta ◽

10.1016/j.placenta.2021.07.020 ◽

2021 ◽

Vol 112 ◽

pp. e6

Author(s):

Vicente Perez-Garcia ◽

Pablo Lopez-Jimenez ◽

Ashley Moffett ◽

Margherita Turco ◽

Myriam Hemberger

Keyword(s):

Trophoblast Differentiation ◽

Human Trophoblast ◽

Sex Combs ◽

Additional Sex Combs

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Comparison of germline mosaics of genes in the Polycomb group of Drosophila melanogaster.

Genetics ◽

10.1093/genetics/140.1.231 ◽

1995 ◽

Vol 140 (1) ◽

pp. 231-243 ◽

Cited By ~ 5

Author(s):

M C Soto ◽

T B Chou ◽

W Bender

Keyword(s):

Drosophila Melanogaster ◽

Target Genes ◽

Cell Types ◽

Mitotic Recombination ◽

Polycomb Group ◽

Specific Cell ◽

Independent Functions ◽

Sex Combs ◽

Null Phenotype ◽

Additional Sex Combs

Abstract The genes of the Polycomb group (PcG) repress the genes of the bithorax and Antennapedia complexes, among others. To observe a null phenotype for a PcG gene, one must remove its maternal as well as zygotic contribution to the embryo. Five members of the PcG group are compared here: Enhancer of Polycomb [E(Pc)], Additional sex combs (Asx), Posterior sex combs (Psc), Suppressor of zeste 2 [Su (z) 2] and Polycomblike (Pcl). The yeast recombinase (FLP) system was used to induce mitotic recombination in the maternal germline. Mutant embryos were analyzed by staining with antibodies against six target genes of the PcG. The loss of the maternal component leads to enhanced homeotic phenotypes and to unique patterns of misexpression. E(Pc) and Su(z) 2 mutations had only subtle effects on the target genes, even when the maternal contributions were removed. Asx and Pcl mutants show derepression of the targets only in specific cell types. Psc shows unusual effects on two of the targets, Ultrabithorax and abdominal-A. These results show that the PcG genes do not act only in a common complex or pathway; they must have some independent functions.

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The Additional sex combs gene of Drosophila encodes a chromatin protein that binds to shared and unique Polycomb group sites on polytene chromosomes

Development ◽

10.1242/dev.125.7.1207 ◽

1998 ◽

Vol 125 (7) ◽

pp. 1207-1216 ◽

Cited By ~ 9

Author(s):

D.A. Sinclair ◽

T.A. Milne ◽

J.W. Hodgson ◽

J. Shellard ◽

C.A. Salinas ◽

...

Keyword(s):

Target Genes ◽

Position Effect ◽

Polytene Chromosomes ◽

Polycomb Group ◽

Position Effect Variegation ◽

Sex Combs ◽

Effect Variegation ◽

The Central Nervous System ◽

Additional Sex Combs ◽

Site Recognition

The Additional sex combs (Asx) gene of Drosophila is a member of the Polycomb group of genes, which are required for maintenance of stable repression of homeotic and other loci. Asx is unusual among the Polycomb group because: (1) one Asx allele exhibits both anterior and posterior transformations; (2) Asx mutations enhance anterior transformations of trx mutations; (3) Asx mutations exhibit segmentation phenotypes in addition to homeotic phenotypes; (4) Asx is an Enhancer of position-effect variegation and (5) Asx displays tissue-specific derepression of target genes. Asx was cloned by transposon tagging and encodes a protein of 1668 amino acids containing an unusual cysteine cluster at the carboxy terminus. The protein is ubiquitously expressed during development. We show that Asx is required in the central nervous system to regulate Ultrabithorax. ASX binds to multiple sites on polytene chromosomes, 70% of which overlap those of Polycomb, polyhomeotic and Polycomblike, and 30% of which are unique. The differences in target site recognition may account for some of the differences in Asx phenotypes relative to other members of the Polycomb group.

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Role of the esc+ gene product in ensuring the selective expression of segment-specific homeotic genes in Drosophila

Development ◽

10.1242/dev.76.1.297 ◽

1983 ◽

Vol 76 (1) ◽

pp. 297-331

Author(s):

Gary Struhl

Keyword(s):

Gene Product ◽

The Body ◽

Homeotic Genes ◽

Bithorax Complex ◽

Sex Combs Reduced ◽

Sex Combs ◽

Correct Determination ◽

Correct Expression

The product of the extra sex combs+ (esc+) gene is required during embryogenesis for the correct determination of segments in Drosophila. If this product is absent, most segments develop like the normal eighth abdominal segment. Here, I extend previous results (Struhl, 1981a) showing that this phenotype results in large part from indiscriminate expression of the bithorax-complex genes which are normally active only in particular segments of the thorax and abdomen. In addition, I test whether the esc+ gene product is required for the correct expression of other homeotic genes. First, I have examined two genes of the Antennapedia-complex (Sex combs reduced+ and Antennapedia+): I find that both genes are normally required in only some of the body segments, but that in the absence of the esc+ gene product, both appear to function adventitiously in other segments. Second, comparing esc+ and esc− embryos lacking both these genes as well as the bithorax-complex, I find that additional homeotic genes (possibly those normally involved in specifying head segments) appear to be expressed indiscriminately when the esc+ gene product is absent. Finally, I present evidence that the products of the esc+ gene and the Polycomb+ gene (a second gene required for the correct regulation of the bithorax-complex) act independently. On the basis of these results, I propose a tentative outline of the roles and realms of action of all of these genes.

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Additional sex combs-likefamily genes are required for normal cardiovascular development

genesis ◽

10.1002/dvg.22793 ◽

2014 ◽

Vol 52 (7) ◽

pp. 671-686 ◽

Cited By ~ 8

Author(s):

Andrea L. McGinley ◽

Yanyang Li ◽

Zane Deliu ◽

Q. Tian Wang

Keyword(s):

Cardiovascular Development ◽

Sex Combs ◽

Additional Sex Combs

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HHEX promotes myeloid transformation in cooperation with mutant ASXL1

Blood ◽

10.1182/blood.2019004613 ◽

2020 ◽

Author(s):

Reina Takeda ◽

Shuhei Asada ◽

Sung-Joon Park ◽

Akihiko Yokoyama ◽

Hans Jiro Becker ◽

...

Keyword(s):

Insertional Mutagenesis ◽

Ectopic Expression ◽

Leukemia Cells ◽

Sex Combs ◽

Integration Sites ◽

The Common ◽

Additional Sex Combs ◽

Induced Apoptosis ◽

Retrovirus Integration ◽

Modest Effect

Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knock-in (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we utilized retrovirus-mediated insertional mutagenesis, which exhibited susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells. In this screening, we identified Hematopoietically expressed homeobox (HHEX) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between ASXL1-MT and HHEX in myeloid leukemogenesis. Expression of HHEX enhanced proliferation of ASXL1-MT expressing HSPCs by inhibiting apoptosis and blocking differentiation, whereas it showed only modest effect in normal HSPCs. Moreover, ASXL1-MT and HHEX accelerated the development of RUNX1-ETO9a and FLT3-ITD leukemia. Conversely, HHEX depletion profoundly attenuated the colony-forming activity and leukemogenicity of ASXL1-MT-expressing leukemia cells. Mechanistically, we identified MYB and ETV5 as downstream targets for ASXL1-MT and HHEX by using transcriptome and ChIP-seq analyses. Moreover, we found that expression of ASXL1-MT enhanced the binding of HHEX to the promoter loci of MYB or ETV5 via reducing H2AK119ub. Depletion of MYB or ETV5 induced apoptosis or differentiation in ASXL1-MT-expressing leukemia cells, respectively. In addition, ectopic expression of MYB or ETV5 reversed the reduced colony-forming activity of HHEX-depleted ASXL1-MT-expressing leukemia cells. These findings indicated that the HHEX-MYB/ETV5 axis promotes myeloid transformation in ASXL1-mutated preleukemia cells.

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A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11

Gene ◽

10.1016/s0378-1119(03)00430-x ◽

2003 ◽

Vol 306 ◽

pp. 115-126 ◽

Cited By ~ 56

Author(s):

C Fisher

Keyword(s):

Human Homolog ◽

Sex Combs ◽

Additional Sex Combs

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Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia

Blood ◽

10.1182/blood-2009-07-230698 ◽

2010 ◽

Vol 115 (1) ◽

pp. 38-46 ◽

Cited By ~ 110

Author(s):

Cynthia L. Fisher ◽

Nicolas Pineault ◽

Christy Brookes ◽

Cheryl D. Helgason ◽

Hideaki Ohta ◽

...

Keyword(s):

Hox Genes ◽

Homeodomain Protein ◽

Loss Of Function ◽

Genomic Amplification ◽

Interaction Domain ◽

Hematopoietic Stem ◽

Amino Terminal ◽

Sex Combs ◽

Additional Sex Combs ◽

Cell Fractions

Abstract The Additional sex combs like 1 (Asxl1) gene is 1 of 3 mammalian homologs of the Additional sex combs (Asx) gene of Drosophila. Asx is unusual because it is required to maintain both activation and silencing of Hox genes in flies and mice. Asxl proteins are characterized by an amino terminal homology domain, by interaction domains for nuclear receptors, and by a C-terminal plant homeodomain protein-protein interaction domain. A recent study of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) revealed a high incidence of truncation mutations that would delete the PHD domain of ASXL1. Here, we show that Asxl1 is expressed in all hematopoietic cell fractions analyzed. Asxl1 knockout mice exhibit defects in frequency of differentiation of lymphoid and myeloid progenitors, but not in multipotent progenitors. We do not detect effects on hematopoietic stem cells, or in peripheral blood. Notably, we do not detect severe myelodysplastic phenotypes or leukemia in this loss-of-function model. We conclude that Asxl1 is needed for normal hematopoiesis. The mild phenotypes observed may be because other Asxl genes have redundant function with Asxl1, or alternatively, MDS or oncogenic phenotypes may result from gain-of-function Asxl mutations caused by genomic amplification, gene fusion, or truncation of Asxl1.

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