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FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing FBXO21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibition of tumor progression, and sensitization to chemotherapy agents. Additionally, knockdown of FBXO21 leads to up-regulation of cytokine signaling pathways. Through a mass spectrometry-based proteomic analysis of FBXO21 in AML, we identified that FBXO21 ubiquitylates p85α, a regulatory subunit of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in decreased PI3K signaling, dimerization of free p85α and ERK activation. These findings reveal the ubiquitin E3 ligase, FBXO21, plays a critical role in regulating AML pathogenesis, specifically through alterations in PI3K via regulation of p85α protein stability.

SUBMITTER: Dobish KK

PROVIDER: S-EPMC10624613 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.

Dobish Kasidy K KK Wittorf Karli J KJ Swenson Samantha A SA Bean Dalton C DC Gavile Catherine M CM Woods Nicholas T NT Ghosal Gargi G Hyde R Katherine RK Buckley Shannon M SM

Leukemia 20230909 11

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing ...[more]

PMID: 37689825

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Project description:ImportanceLeukemia cutis (LC) is an important yet understudied extramedullary manifestation of leukemia. Previous reports have suggested poor prognosis for patients with LC, but these reports have largely consisted of descriptive studies with a limited number of patients.ObjectivesTo identify patient factors associated with LC and characterize the association of LC with the course of acute myeloid leukemia (AML).Design, setting, and participantsThis retrospective, matched-cohort study included 1683 patients with AML diagnosed from January 1, 2005, to April 1, 2017, with and without biopsy-proven LC seen at a single-center, tertiary care hospital in St Louis, Missouri. To specifically evaluate differences in survival, propensity scoring was used to match patients with AML with LC to patients with AML without LC off the logit of propensity score based on age, race/ethnicity, sex, and leukemia type. Kaplan-Meier methods were used to compare cumulative probability survival. Matched survival analysis was performed with extended Cox regression to determine factors associated with leukemia-specific and overall survival.Main outcomes and measuresLeukemia-specific survival and overall survival.ResultsA total of 1683 patients were reviewed, including 78 patients with biopsy-proven LC of the AML type and 1605 patients with AML without LC. A total of 62 of the patients with AML and LC (mean [SD] age, 58.2 [11.7] years; 33 [53.2%] male) were matched in a 1:3 ratio to 186 patients with AML without LC (mean [SD] age, 58.2 [13.5] years; 103 [55.4%] male). The 5-year survival among the 62 patients with AML with LC was 8.6%, shorter than the 28.3% among the 186 matched patients with AML without LC. Matched survival analysis revealed that patients with AML and LC compared with those without LC had hazard ratios of 2.06 (95% CI, 1.26-3.38; P = .004) for leukemia-specific death and of 1.66 (95% CI, 1.06-2.60; P = .03) for all-cause death. In addition, matched patients with LC had greater odds of extramedullary organ burden (odds ratio, 3.48; 95% CI, 1.72-7.05; P < .001).Conclusions and relevanceThe results suggest that the presentation of LC in patients with AML is associated with decreased overall survival and leukemia-specific survival. Patients with AML presenting with LC may require more intensive treatment and monitoring of their leukemic disease.

Dataset Information

FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.

Publications

FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.

Similar Datasets

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