Loss of FBXO9 enhances proteasome activity and promotes aggressiveness in acute myeloid leukemia

Abstract

word count : 192 28 Text word count : 3948 29 30 31 2 ABSTRACT 32The hematopoietic system is maintained throughout life by hematopoietic stem cells that are 33 capable of differentiating into all hematopoietic lineages. An intimate balance between self-34 renewal, differentiation, and quiescence is required to maintain hematopoiesis. Disruption of this 35 balance can result in hematopoietic malignancy, including acute myeloid leukemia (AML). 36FBXO9, from the F-box E3 ubiquitin ligases, is down-regulated in patients with AML compared 37 to normal bone marrow. FBXO9 is the substrate recognition component of the Skp1-Cullin-F-38 box (SCF)-type E3 ligase complex. FBXO9 is highly expressed in hematopoietic stem and 39 progenitor populations, which contain the tumor-initiating population in AML. In AML patients, 40 decrease in FBXO9 expression is most pronounced in patients with the inversion of 41 chromosome 16 (inv (16)), a rearrangement that generates the transcription factor fusion gene, 42CBFB-MYH11. To study FBXO9 in malignant hematopoiesis, we generated a conditional 43 knockout mouse model using a novel CRISPR/Cas9 strategy. Our data show that deletion of 44 Fbxo9 in mice expressing Cbfb-MYH11 leads to markedly accelerated and aggressive leukemia 45 development. In addition, we find loss of FBXO9 leads to increased proteasome expression and 46 tumors are more sensitive to bortezomib suggesting that FBXO9 expression may predict patient 47 response to bortezomib treatment. 48 49 50 3 INTRODUCTION 51Acute myeloid leukemia (AML) is a hematologic malignancy resulting in an accumulation of 52 immature myeloid blasts impairing normal hematopoiesis 1 . This disease accounts for 35% of 53 new leukemia diagnoses and 48% of leukemia-related deaths 2 . In 2019, AML is estimated to be 54 the most frequently diagnosed leukemia and the only common form with a higher mortality rate 55 than incidence. Although new therapies have recently been approved, they are limited to 56 specific subtypes of AML and only increase the treatment options for limited subsets of 57 patients 3-6 . To develop more effective and less toxic therapies for use across multiple subtypes, 58we must better understand the mechanisms underlying development and progression of AML. 60One system that has not been extensively studied in the context of AML is the ubiquitin 61 proteasome system (UPS). The UPS coordinates the degradation of proteins globally and 62 compartmentally within a cell and is a key regulatory mechanism for many cellular processes 63 including cell cycle, transcription, and proliferation 7 . Two main components of this system are 64 the E3 ubiquitin ligases that determine substrate specificity and the 26S proteasome 65 responsible for protein degradation. This system has proven to be a viable target in hematologic 66 malignances either through targeting the 26S proteasome with drugs such as bortezomib 8 or by 67 altering substrate recognition of E3 ligases as is done with thalidomide 9 . The successful 68 utilization of these drugs in oth...

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“… 40 Loss of FBXO9 accelerated the progression of acute myeloid leukemia, serving as a tumor suppressor in acute myeloid leukemia. 41 FBXO15 has been reported to be a critical gene in maintaining normal development and physiology in mice. 19 The knockdown of FBXO15 increased cancer-associated drug resistance by P-glycoprotein accumulation.…”