Abstract
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 reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances 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 therapeutic approach for inv(16) AML.
Highlights
Wei-Kai Hua1, Qi Cai1, Emily Carnahan1, Wei Chen4, Xiwei Wu4, Piotr Swiderski5, Russell C
Inv[16] disrupts the CBFB gene encoding the CBFβ subunit of the corebinding factor (CBF) transcription factor complex that acts as a master regulator of hematopoietic development and lineage specification9,10
We recently reported that activating tyrosine kinase mutations (e.g., BCR-ABL, FLT3-ITD) deregulate intronic miRNA biogenesis by interfering with RANXPO5 mediated pre-miRNA processing via phosphorylation of SPRED1, a member of the Sprouty family of proteins30,31
Summary
Acute myeloid leukemia (AML) harboring inv[16](p13q22) expresses high levels of miR-126. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv[16] AML murine and xenograft models. Inv[16] disrupts the CBFB gene encoding the CBFβ subunit of the corebinding factor (CBF) transcription factor complex that acts as a master regulator of hematopoietic development and lineage specification. Inv[16] AML patients have a relatively favorable prognosis, only approximately 50–60% eventually achieve long-term survival with standard chemotherapy. MiR126 expression is enriched in long-term hematopoietic stem cells (HSCs) and plays a pivotal role in restraining cell cycle progression and maintaining HSC quiescence. We recently reported that activating tyrosine kinase mutations (e.g., BCR-ABL, FLT3-ITD) deregulate intronic miRNA (e.g., miR-126) biogenesis by interfering with RANXPO5 mediated pre-miRNA processing via phosphorylation of SPRED1, a member of the Sprouty family of proteins
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
