Open Collections

The role of FBXO11 in human hematopoiesis

University of British Columbia

Acute myeloid leukemia (AML) is an aggressive blood disease associated with complex mutational patterns. Our previous AML sequencing study has revealed frequent somatic mutations in ubiquitin proteasome system (UPS) genes, with recurrent loss-of-function mutations in FBXO11, which codes substrate-recognition component for E3 ubiquitin ligase complex. Our mouse transplant model shows a biological cooperation between Fbxo11 knockdown and enforced AML1-ETO expression in driving mouse leukemogenesis. However, to-date the role of FBXO11 depletion in contributing to human leukemogenesis remains unclear. Gene set enrichment analysis (GSEA) on microarray data of FBXO11-knockdown human hematopoietic stem and progenitor cells (HSPCs) revealed a significant enrichment in stem cell signature, and dysregulated pathways centered on hypoxia and delay in cell cycle progression. Our work further shows that FBXO11 loss confers quiescence while enhancing more primitive populations ex vivo. Co-occurrence and exclusivity of UPS gene mutations with other frequent variants in AML were previously computed and reveal a significantly strong trend of RAS mutations co-occurring with UPS mutations in leukemogenesis. Given that FBXO11 knockdown confers quiescence on human HSPCs ex vivo and AML emerges as a heterogeneous disease with complex co-mutation patterns, we investigated in parallel the effect of KRASG12D (K) and AML1-ETO (A) alone and in combination with FBXO11 knockdown, to examine whether FBXO11 depletion can cooperate with leukemia-associated oncogenes to initiate AML in a xenograft model. Our results show that FBXO11 depletion restrains the growth of KA cells ex vivo, possibly through delaying G₀ exit, while enhancing their in vivo repopulating capacity, potentially leading to leukemogenesis.

Text

2022-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75256

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/