ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias
Abstract Deletion of ABL1 was detected in a cohort of hematologic malignancies carrying AML1-ETO and NUP98 fusion proteins. Abl1−/− murine hematopoietic cells transduced with AML1-ETO and NUP98-PMX1 gained proliferation advantage when compared to Abl1 + /+ counterparts. Conversely, overexpression an...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-03-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-023-00810-0 |
| _version_ | 1827979599414296576 |
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| author | Konstantin Golovine Gleb Abalakov Zhaorui Lian Srinivas Chatla Adam Karami Kumaraswamy Naidu Chitrala Jozef Madzo Margaret Nieborowska-Skorska Jian Huang Tomasz Skorski |
| author_facet | Konstantin Golovine Gleb Abalakov Zhaorui Lian Srinivas Chatla Adam Karami Kumaraswamy Naidu Chitrala Jozef Madzo Margaret Nieborowska-Skorska Jian Huang Tomasz Skorski |
| author_sort | Konstantin Golovine |
| collection | DOAJ |
| description | Abstract Deletion of ABL1 was detected in a cohort of hematologic malignancies carrying AML1-ETO and NUP98 fusion proteins. Abl1−/− murine hematopoietic cells transduced with AML1-ETO and NUP98-PMX1 gained proliferation advantage when compared to Abl1 + /+ counterparts. Conversely, overexpression and pharmacological stimulation of ABL1 kinase resulted in reduced proliferation. To pinpoint mechanisms facilitating the transformation of ABL1-deficient cells, Abl1 was knocked down in 32Dcl3-Abl1ko cells by CRISPR/Cas9 followed by the challenge of growth factor withdrawal. 32Dcl3-Abl1ko cells but not 32Dcl3-Abl1wt cells generated growth factor-independent clones. RNA-seq implicated PI3K signaling as one of the dominant mechanisms contributing to growth factor independence in 32Dcl3-Abl1ko cells. PI3K inhibitor buparlisib exerted selective activity against Lin-cKit+ NUP98-PMX1;Abl1−/− cells when compared to the Abl1 + /+ counterparts. Since the role of ABL1 in DNA damage response (DDR) is well established, we also tested the inhibitors of ATM (ATMi), ATR (ATRi) and DNA-PKcs (DNA-PKi). AML1-ETO;Abl1−/− and NUP98-PMX1;Abl1−/− cells were hypersensitive to DNA-PKi and ATRi, respectively, when compared to Abl1 + /+ counterparts. Moreover, ABL1 kinase inhibitor enhanced the sensitivity to PI3K, DNA-PKcs and ATR inhibitors. In conclusion, we showed that ABL1 kinase plays a tumor suppressor role in hematological malignancies induced by AML1-ETO and NUP98-PMX1 and modulates the response to PI3K and/or DDR inhibitors. |
| first_indexed | 2024-04-09T21:39:15Z |
| format | Article |
| id | doaj.art-9b3ccc35e2f64fd183c31210d078e826 |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-04-09T21:39:15Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-9b3ccc35e2f64fd183c31210d078e8262023-03-26T11:06:58ZengNature Publishing GroupBlood Cancer Journal2044-53852023-03-011311710.1038/s41408-023-00810-0ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemiasKonstantin Golovine0Gleb Abalakov1Zhaorui Lian2Srinivas Chatla3Adam Karami4Kumaraswamy Naidu Chitrala5Jozef Madzo6Margaret Nieborowska-Skorska7Jian Huang8Tomasz Skorski9Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineFels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineCoriell Institute for Medical ResearchFels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineFels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineFels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineCoriell Institute for Medical ResearchFels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineCoriell Institute for Medical ResearchFels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of MedicineAbstract Deletion of ABL1 was detected in a cohort of hematologic malignancies carrying AML1-ETO and NUP98 fusion proteins. Abl1−/− murine hematopoietic cells transduced with AML1-ETO and NUP98-PMX1 gained proliferation advantage when compared to Abl1 + /+ counterparts. Conversely, overexpression and pharmacological stimulation of ABL1 kinase resulted in reduced proliferation. To pinpoint mechanisms facilitating the transformation of ABL1-deficient cells, Abl1 was knocked down in 32Dcl3-Abl1ko cells by CRISPR/Cas9 followed by the challenge of growth factor withdrawal. 32Dcl3-Abl1ko cells but not 32Dcl3-Abl1wt cells generated growth factor-independent clones. RNA-seq implicated PI3K signaling as one of the dominant mechanisms contributing to growth factor independence in 32Dcl3-Abl1ko cells. PI3K inhibitor buparlisib exerted selective activity against Lin-cKit+ NUP98-PMX1;Abl1−/− cells when compared to the Abl1 + /+ counterparts. Since the role of ABL1 in DNA damage response (DDR) is well established, we also tested the inhibitors of ATM (ATMi), ATR (ATRi) and DNA-PKcs (DNA-PKi). AML1-ETO;Abl1−/− and NUP98-PMX1;Abl1−/− cells were hypersensitive to DNA-PKi and ATRi, respectively, when compared to Abl1 + /+ counterparts. Moreover, ABL1 kinase inhibitor enhanced the sensitivity to PI3K, DNA-PKcs and ATR inhibitors. In conclusion, we showed that ABL1 kinase plays a tumor suppressor role in hematological malignancies induced by AML1-ETO and NUP98-PMX1 and modulates the response to PI3K and/or DDR inhibitors.https://doi.org/10.1038/s41408-023-00810-0 |
| spellingShingle | Konstantin Golovine Gleb Abalakov Zhaorui Lian Srinivas Chatla Adam Karami Kumaraswamy Naidu Chitrala Jozef Madzo Margaret Nieborowska-Skorska Jian Huang Tomasz Skorski ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias Blood Cancer Journal |
| title | ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias |
| title_full | ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias |
| title_fullStr | ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias |
| title_full_unstemmed | ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias |
| title_short | ABL1 kinase as a tumor suppressor in AML1-ETO and NUP98-PMX1 leukemias |
| title_sort | abl1 kinase as a tumor suppressor in aml1 eto and nup98 pmx1 leukemias |
| url | https://doi.org/10.1038/s41408-023-00810-0 |
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