FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML
Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.696532/full |
| _version_ | 1818610992606609408 |
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| author | Mikhail S Chesnokov Soheila Borhani Marianna Halasi Marianna Halasi Zarema Arbieva Irum Khan Andrei L. Gartel |
| author_facet | Mikhail S Chesnokov Soheila Borhani Marianna Halasi Marianna Halasi Zarema Arbieva Irum Khan Andrei L. Gartel |
| author_sort | Mikhail S Chesnokov |
| collection | DOAJ |
| description | Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients. |
| first_indexed | 2024-12-16T15:23:15Z |
| format | Article |
| id | doaj.art-128ccb8058454ea3b7ac81ca8046d6b0 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-16T15:23:15Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-128ccb8058454ea3b7ac81ca8046d6b02022-12-21T22:26:33ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-07-011110.3389/fonc.2021.696532696532FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AMLMikhail S Chesnokov0Soheila Borhani1Marianna Halasi2Marianna Halasi3Zarema Arbieva4Irum Khan5Andrei L. Gartel6Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Surgery, Massachusetts General Hospital, Boston, MA, United StatesGenome Research Core, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesForkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.https://www.frontiersin.org/articles/10.3389/fonc.2021.696532/fullFOXM1AKT pathwayacute myeloid leukemiapositive feedback loopdrug resistanceHOXA gene family |
| spellingShingle | Mikhail S Chesnokov Soheila Borhani Marianna Halasi Marianna Halasi Zarema Arbieva Irum Khan Andrei L. Gartel FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML Frontiers in Oncology FOXM1 AKT pathway acute myeloid leukemia positive feedback loop drug resistance HOXA gene family |
| title | FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML |
| title_full | FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML |
| title_fullStr | FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML |
| title_full_unstemmed | FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML |
| title_short | FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML |
| title_sort | foxm1 akt positive regulation loop provides venetoclax resistance in aml |
| topic | FOXM1 AKT pathway acute myeloid leukemia positive feedback loop drug resistance HOXA gene family |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.696532/full |
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