Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA762718 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15864327.fastq.gz | Fastqsanger.gz | |||
| SRR15864328.fastq.gz | Fastqsanger.gz | |||
| SRR15864329.fastq.gz | Fastqsanger.gz | |||
| SRR15864330.fastq.gz | Fastqsanger.gz | |||
| SRR15864331.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.
2021-09-15 | GSE184015 | GEO
Project description: Not available
| S-EPMC8536759 | biostudies-literature
Project description:Core binding factor (CBF) acute myeloid leukemias most commonly harbor the translocations t(8;21) or inv(16). Cohesin mutations are less commonly observed in inv(16) than in t(8;21), suggesting that they may negatively impact leukemic initiation or maintenance in this setting. We used a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3 and paradoxically found that inv(16);Smc3D/+ mice have a reduced leukemic latency compared to inv(16);Smc3+/+ mice, suggesting a role for cohesin loss in leukemic initiation or maintenance. Given the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16);Smc3 D/+ HSPCs prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. We also observe an increase in Fli1 expression and enhanced Fli1 target expression in the most primitive hematopoietic stem cells using scRNA-seq, linking enhanced Fli1 activity in the inv(16);Smc3D/+ setting to leukemic initiation consistent with elevated RAS activity, which is common in inv(16) AML. We further show that Fli1 is essential for the maintenance stage of inv(16);Smc3D/+ AML. Our data demonstrate that cohesin loss drives both leukemic initiation and maintenance in inv(16) AML, identifying Fli1 as a previously unrecognized therapeutic vulnerability.
2026-07-16 | GSE329080 | GEO
Project description:Core binding factor (CBF) acute myeloid leukemias most commonly harbor the translocations t(8;21) or inv(16). Cohesin mutations are less commonly observed in inv(16) than in t(8;21), suggesting that they may negatively impact leukemic initiation or maintenance in this setting. We used a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3 and paradoxically found that inv(16);Smc3D/+ mice have a reduced leukemic latency compared to inv(16);Smc3+/+ mice, suggesting a role for cohesin loss in leukemic initiation or maintenance. Given the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16);Smc3 D/+ HSPCs prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. We also observe an increase in Fli1 expression and enhanced Fli1 target expression in the most primitive hematopoietic stem cells using scRNA-seq, linking enhanced Fli1 activity in the inv(16);Smc3D/+ setting to leukemic initiation consistent with elevated RAS activity, which is common in inv(16) AML. We further show that Fli1 is essential for the maintenance stage of inv(16);Smc3D/+ AML. Our data demonstrate that cohesin loss drives both leukemic initiation and maintenance in inv(16) AML, identifying Fli1 as a previously unrecognized therapeutic vulnerability.
2026-07-16 | GSE286946 | GEO
Project description:Core binding factor (CBF) acute myeloid leukemias most commonly harbor the translocations t(8;21) or inv(16). Cohesin mutations are less commonly observed in inv(16) than in t(8;21), suggesting that they may negatively impact leukemic initiation or maintenance in this setting. We used a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3 and paradoxically found that inv(16);Smc3D/+ mice have a reduced leukemic latency compared to inv(16);Smc3+/+ mice, suggesting a role for cohesin loss in leukemic initiation or maintenance. Given the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16);Smc3 D/+ HSPCs prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. We also observe an increase in Fli1 expression and enhanced Fli1 target expression in the most primitive hematopoietic stem cells using scRNA-seq, linking enhanced Fli1 activity in the inv(16);Smc3D/+ setting to leukemic initiation consistent with elevated RAS activity, which is common in inv(16) AML. We further show that Fli1 is essential for the maintenance stage of inv(16);Smc3D/+ AML. Our data demonstrate that cohesin loss drives both leukemic initiation and maintenance in inv(16) AML, identifying Fli1 as a previously unrecognized therapeutic vulnerability.
2026-07-16 | GSE286322 | GEO
Project description:Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion CBF::MYH11 oncoprotein regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBF::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBF::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.
2024-11-18 | GSE215613 | GEO
Project description:Acute myeloid leukemia (AML) with inv(16) is typically associated to a favourable prognosis. However, up to 40% of patients will eventually experience disease relapse. Herein, we dissected the transcriptomic profile of AML with inv(16) to identify potential prognostic markers and devise novel therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed the presence of a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not significantly differ between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic and relapse) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on ME-1 inv(16) cell-line, but there was no additional advantage in terms of proliferation suppression over Azacitidine alone. To enhance Venetoclax efficacy, we tested the in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusion, the study of transcriptomic features of inv(16) at relapse unveiled OXPHOS as a potential target in this subset. The use of specific metabolic-oriented and synthetic lethal approaches (e.g., Venetoclax/Metformin) provided a rationale for its future clinical use.
2026-06-30 | GSE254098 | GEO
Project description:inv(16)/Tet2-/- GMPs (Lin- Sca1- ckit+ CD41- FcgR+ CD150-) were FACS sorted as described in Supplementary Information (Reckzeh, K et al 2020) TET2 deficiency cooperates with CBFB-MYH11 to induce acute myeloid leukemia and represents an early leukemogenic event. Reckzeh, K et al.
2022-03-28 | GSE161390 | GEO
Project description:Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia
| PRJNA1068555 | ENA
Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC.
2016-03-31 | PXD001994 | Pride