Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome.
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ABSTRACT:
SUBMITTER: Varney ME
PROVIDER: S-EPMC5729588 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
Publications
Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome.
Varney M E ME Choi K K Bolanos L L Christie S S Fang J J Grimes H L HL Maciejewski J P JP Inoue J-I JI Starczynowski D T DT
Leukemia 20161003 2
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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.
2016-09-29 | GSE87453 | GEO
Project description:BackgroundTo estimate real-world outcomes in East Asian populations, we conducted a nationwide retrospective analysis of the efficacy and safety of lenalidomide for del(5q) myelodysplastic syndrome (MDS) patients with transfusion-dependent anemia in Korea.MethodsPatients aged ≥19 years who had received lenalidomide for the treatment of lower-risk, red blood cell (RBC) transfusion-dependent del(5q) MDS were selected. A filled case report form (CRF) with information from electronic medical records was requested from members of the acute myeloid leukemia (AML)/MDS Working Party of the Korean Society of Hematology. All the CRFs were gathered and analyzed.ResultsA total of 31 patients were included in this study. Of 28 evaluable patients, 19 (67.9%) achieved RBC transfusion independence (RBC-TI). Female sex and the development of thrombocytopenia during treatment were associated with achieving RBC-TI. The most common non-hematologic toxicities were pruritus, fatigue, and rashes. All non-hematologic toxicities of grades ≥3 were limited to rash (12.9%) and pruritus (6.5%). Dose reduction was required in 15 of the 19 responders (78.9%). The most common final stable dosing schedule for the responders was 5 mg once every other day (31.6%).ConclusionLenalidomide efficacy and tolerability were similar in the Asian del(5q) MDS patients and western patients. Dose reduction during treatment was common, but it was not associated with inferior outcomes.
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Project description:The most common chromosomal abnormalities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are -5/del(5q) and -7/del(7q). When -5/del(5q) and -7/del(7q) coexist in patients, a poor prognosis is typically associated. Given that -5/del(5q) and/or -7/del(7q) often are accompanied with additional recurrent chromosomal alterations, genetic change(s) on the accompanying chromosome(s) other than chromosomes 5 and 7 may be important factor(s) affecting leukemogenesis and disease prognosis. Using an integrated analysis of karyotype, FISH and array CGH results in this study, we evaluated the smallest region of overlap (SRO) of chromosomes 5 and 7 as well as copy number alterations (CNAs) on the other chromosomes. Moreover, the relationship between the CNAs and del(5q) and -7/del(7q) was investigated by categorizing the cases into three groups based on the abnormalities of chromosomes 5 and 7 [group I: cases only with del(5q), group II: cases only with -7/del(7q) and group III: concurrent del(5q) and del(7q) cases]. The overlapping SRO of chromosome 5 from groups I and III was 5q31.1-33.1 and of chromosome 7 from groups II and III was 7q31.31-q36.1. A total of 318 CNAs were observed; ~ 78.3% of them were identified on chromosomes other than chromosomes 5 and 7, which were defined as 'other CNAs'. Group III was a distinctive group carrying the most high number (HN) CNAs, cryptic CNAs and 'other CNAs'. The loss of TP53 was highly associated with del(5q). The loss of ETV6 was specifically associated with group III. These CNAs or genes may play a secondary role in disease progression and should be further evaluated for their clinical significance and influence on therapeutic approaches in patients with MDS/AML carrying del(5q) and/or -7/del(7q) in large-scale, patient population study.
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Project description:We examined whether lenalidomide exposure up-regulates miRNAs and mRNAs, previously shown to play a role in the disease phenotype of del(5q) myelodysplastic syndrome, in pre-treatment CD34(+) marrow cells. We hypothesized that increased expression would predict for clinical response. Changes in miR-143, miR-145, miR-146a, miR-146b, miR-378, miR-584, SPARC and RPS14 were examined in del(5q) (n=10) and non-del(5q) (n=18) myelodysplastic syndrome patient samples. Significantly increased expression of miR-143 (1.8-fold and 1.5-fold in del(5q) and non-del(5q), respectively), and miR-145 (1.9-fold and 1.6-fold in del(5q) and non-del(5q), respectively) was observed. In the del(5q) myelodysplastic syndrome cohort, transfusion independence correlated with a 1.3-fold or more increase in miR-145 expression and response over 12 months correlated with a 1.5-fold or more increase. Knockdown of miR-143 and miR-145 in cord blood CD34(+) cells resulted in increased erythroid progenitor activity. Lenalidomide selectively abrogated progenitor activity in cells depleted of miR-143 and miR-145 supporting a key role for miR-143/145 in the sensitivity to lenalidomide of del(5q) myelodysplastic syndrome patients.
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Project description:TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.
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