Haploinsufficiency of multiple del(5q) genes induce B cell abnormalities in mice.
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ABSTRACT:
SUBMITTER: Liu T
PROVIDER: S-EPMC7768807 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Haploinsufficiency of multiple del(5q) genes induce B cell abnormalities in mice.
Liu Tuoen T Ahmed Tanzir T Krysiak Kilannin K Shirai Cara Lunn CL Shao Jin J Nunley Ryan R Bucala Richard R McKenzie Andrew A Ndonwi Matthew M Walter Matthew J MJ
Leukemia research 20200723
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Project description:Monosomy 5 and deletions of the chromosome 5q (-5/del(5q)) are recurrent events in de novo adult acute myeloid leukemia (AML), reaching up to 40% of cases in secondary AML. These chromosome anomalies are associated with TP53 mutations and with very poor prognosis. Using the large Leucegene genomic and transcriptomic dataset composed of 48 -5/del(5q) patient specimens and 367 control AML, we identified DELE1 - located in the common deleted region - as the most consistently downregulated gene in these leukemias. DELE1 encodes a mitochondrial protein recently characterized as the relay of mitochondrial stress to the cytosol through a newly defined OMA1-DELE1-HRI pathway which ultimately leads to the activation of ATF4, the master transcription factor of the integrated stress response. Here, we showed that the partial loss of DELE1 expression observed in -5/del(5q) patients was sufficient to significantly reduce the sensitivity to mitochondrial stress in AML cells. Overall, our results suggest that DELE1 haploinsufficiency could represent a new driver mechanism in -5/del(5q) AML.
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Project description:Loss of a whole chromosome 5 or a deletion of the long arm, del(5q), is a recurring abnormality in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). To identify a leukemia-related gene on chromosome 5, we previously delineated a 970-kb segment of 5q31 that is deleted in all patients examined, and prepared a transcript map of this region. EGR1 is a candidate tumor suppressor gene within the commonly deleted segment of 5q, and encodes a zinc finger transcription factor. To test the hypothesis that loss of function of Egr1 is an initiating event in the pathogenesis of AML/MDS, Egr1-deficient mice were treated with a potent DNA alkylating agent, N-ethyl-nitrosourea (ENU), to induce secondary cooperating mutations. Egr1(+/-) and Egr1(-/-) mice treated with ENU developed immature T-cell lymphomas (CD4(+), CD8(+)) or a myeloproliferative disorder (MPD) at increased rates and with shorter latencies than that of wild-type littermates. The MPD was characterized by an elevated white blood cell count, anemia, and thrombocytopenia with ineffective erythropoiesis. Biallelic mutations of Egr1 were not observed in MPDs in Egr1(+/-) mice. Our data suggest that haploinsufficiency for Egr1 plays a role in murine leukemogenesis, and in the development of AML/MDS characterized by abnormalities of chromosome 5.
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Project description:Background: Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of RAI1 are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Methods: To investigate the relationship between Rai1 and social impairment, we evaluated the Rai1+/- mice with a battery of tests to address social behavior in mice. Results: We found that the mutant mice showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors when compared to wild type littermates. Conclusions: These findings suggest that Rai1 contributes to social behavior in mice, and prompt it as a candidate gene for the social behaviors observed in Smith-Magenis Syndrome patients.
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Project description:Interstitial deletion of a single copy of chromosome 5q is the most frequent cytogenetic alteration in Myelodysplastic Syndromes (MDS), which results in reduced dosage of numerous genes. Furthermore, the extent of the 5q deletion determines disease severity, suggesting cooperation between deleted genes in the proximal and distal regions of del(5q). Although the contribution of individual genes to the pathogenesis of del(5q) MDS has been investigated, less is known about the epistatic interactions and/or cooperation between neighboring deleted genes. Deletion of TRAF-interacting protein with forkhead-associated domain B (TIFAB) and miR-146a, two haploinsufficient genes in del(5q) MDS, has been previously reported to activate the Toll-like receptor (TLR) signaling cascade in hematopoietic stem/progenitor cells (HSPC) by increasing TRAF6 protein stability and mRNA translation, respectively. To investigate the epistasis of TIFAB and miR-146a, we generated a mouse model in which Tifab and miR-146a were simultaneously deleted (Tifab-/-;miR-146a-/-, dKO). Herein, we report that combined hematopoietic-specific deletion of Tifab and miR-146a results in more rapid and severe cytopenia, and progression to a fatal bone marrow (BM) failure-like disease as compared to Tifab- or miR-146adeficiency alone. HSPC from Tifab-/-, miR-146a-/-, and dKO mice exhibit enrichment of gene 69 regulatory networks associated with innate immune signaling. Moreover, a subset of the differentially expressed genes is controlled synergistically following deletion of Tifab and miR-146a. Notably, nearly half of these defined synergy response genes identified in the mouse models were aberrantly expressed in del(5q) MDS HSPC when TIFAB (5q31) and miR-146a (5q33.3) were both deleted. Thus, synergistic control of gene expression following deletion of epistatic haploinsufficient genes in del(5q) MDS may be an underlying mechanism of the diseased state.
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