Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia
Abstract Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML pat...
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| Format: | Article |
| Language: | English |
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Wiley
2024-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202305885 |
| _version_ | 1797255034244694016 |
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| author | Jie Jin Shangyu Hou Yiyi Yao Miaomiao Liu Liping Mao Min Yang Hongyan Tong Tao Zeng Jinyan Huang Yinghui Zhu Huafeng Wang |
| author_facet | Jie Jin Shangyu Hou Yiyi Yao Miaomiao Liu Liping Mao Min Yang Hongyan Tong Tao Zeng Jinyan Huang Yinghui Zhu Huafeng Wang |
| author_sort | Jie Jin |
| collection | DOAJ |
| description | Abstract Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV‐sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV‐susceptible and DA‐resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA‐resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL‐1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML. |
| first_indexed | 2024-04-24T21:59:26Z |
| format | Article |
| id | doaj.art-d4df7197437c45e699dacf40e008671b |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T21:59:26Z |
| publishDate | 2024-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-d4df7197437c45e699dacf40e008671b2024-03-20T12:56:12ZengWileyAdvanced Science2198-38442024-03-011111n/an/a10.1002/advs.202305885Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid LeukemiaJie Jin0Shangyu Hou1Yiyi Yao2Miaomiao Liu3Liping Mao4Min Yang5Hongyan Tong6Tao Zeng7Jinyan Huang8Yinghui Zhu9Huafeng Wang10Department of Hematology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 P. R. ChinaResearch Center for Translational Medicine Shanghai East Hospital School of Life Sciences and Technology Tongji University Shanghai 200092 P.R. ChinaDepartment of Hematology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 P. R. ChinaResearch Center for Translational Medicine Shanghai East Hospital School of Life Sciences and Technology Tongji University Shanghai 200092 P.R. ChinaDepartment of Hematology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 P. R. ChinaDepartment of Hematology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 P. R. ChinaDepartment of Hematology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 P. R. ChinaBiomedical big data center the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang 310003 P.R. ChinaBiomedical big data center the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang 310003 P.R. ChinaResearch Center for Translational Medicine Shanghai East Hospital School of Life Sciences and Technology Tongji University Shanghai 200092 P.R. ChinaDepartment of Hematology the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 P. R. ChinaAbstract Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV‐sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV‐susceptible and DA‐resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA‐resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL‐1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.https://doi.org/10.1002/advs.202305885acute myeloid leukemiaAKT1AURKBdrug resistancevenetoclax |
| spellingShingle | Jie Jin Shangyu Hou Yiyi Yao Miaomiao Liu Liping Mao Min Yang Hongyan Tong Tao Zeng Jinyan Huang Yinghui Zhu Huafeng Wang Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia Advanced Science acute myeloid leukemia AKT1 AURKB drug resistance venetoclax |
| title | Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia |
| title_full | Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia |
| title_fullStr | Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia |
| title_full_unstemmed | Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia |
| title_short | Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia |
| title_sort | phosphoproteomic characterization and kinase signature predict response to venetoclax plus 3 7 chemotherapy in acute myeloid leukemia |
| topic | acute myeloid leukemia AKT1 AURKB drug resistance venetoclax |
| url | https://doi.org/10.1002/advs.202305885 |
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