Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia
Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provid...
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| Format: | Article |
| Language: | English |
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Ferrata Storti Foundation
2024-12-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/11876 |
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| author | Shanna M. Hogeling Duy Minh Lê Nikita La Rose Min Chul Kwon Albertus T.J. Wierenga Fiona A.J. van den Heuvel Vincent van den Boom Anna Kuchnio Ulrike Philippar Gerwin Huls Jan Jacob Schuringa |
| author_facet | Shanna M. Hogeling Duy Minh Lê Nikita La Rose Min Chul Kwon Albertus T.J. Wierenga Fiona A.J. van den Heuvel Vincent van den Boom Anna Kuchnio Ulrike Philippar Gerwin Huls Jan Jacob Schuringa |
| author_sort | Shanna M. Hogeling |
| collection | DOAJ |
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Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provides an attractive opportunity to impair long-term proliferation and induce differentiation. The novel inhibitor JNJ- 75276617 (bleximenib) targets the menin-KMT2A interaction and provides preclinical efficacy in AML (Kwon et al1). Here, we provide mechanistic insight in how JNJ- 75276617 impairs proliferation and drives differentiation of primary AML patient cells. A large-scale drug screen was set up in which genetic alterations and quantitative proteomics were compared with drug sensitivity in a preclinical setting, which revealed that granulocyte macrophage progenitor (GMP)-like AMLs display the greatest sensitivity. Furthermore, we identified that NPM1c/DNMT3Amut AMLs are sensitive, and some NPM1wt AML subtypes without KMT2A-MLLT3 rearrangements benefit from menin-KMT2A inhibition. Genome-wide ChIP-seq studies revealed patient-specific epigenetic alterations upon JNJ-75276617 treatment, uncovering a striking upregulation of MHC class I and class II expression as a consequence of epigenetic changes upon menin-KMT2A inhibition, independent of MEIS1 loss but involving CIITA activation. Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery.
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| format | Article |
| id | doaj-art-b12e34c2d21c432d86cb3d9b8a8be138 |
| institution | Kabale University |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-b12e34c2d21c432d86cb3d9b8a8be1382024-12-19T19:43:19ZengFerrata Storti FoundationHaematologica0390-60781592-87212024-12-01999110.3324/haematol.2024.285616Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemiaShanna M. Hogeling0Duy Minh Lê1Nikita La Rose2Min Chul Kwon3Albertus T.J. Wierenga4Fiona A.J. van den Heuvel5Vincent van den Boom6Anna Kuchnio7Ulrike Philippar8Gerwin Huls9Jan Jacob Schuringa10Department of Hematology, University Medical Center Groningen, University of Groningen, GroningenDepartment of Hematology, University Medical Center Groningen, University of Groningen, GroningenDepartment of Hematology, University Medical Center Groningen, University of Groningen, GroningenDiscovery Oncology, Janssen RD, BeerseDepartment of Hematology, University Medical Center Groningen, University of Groningen, GroningenDepartment of Hematology, University Medical Center Groningen, University of Groningen, GroningenDepartment of Hematology, University Medical Center Groningen, University of Groningen, GroningenDiscovery Oncology, Janssen RD, BeerseDiscovery Oncology, Janssen RD, BeerseDepartment of Hematology, University Medical Center Groningen, University of Groningen, GroningenDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provides an attractive opportunity to impair long-term proliferation and induce differentiation. The novel inhibitor JNJ- 75276617 (bleximenib) targets the menin-KMT2A interaction and provides preclinical efficacy in AML (Kwon et al1). Here, we provide mechanistic insight in how JNJ- 75276617 impairs proliferation and drives differentiation of primary AML patient cells. A large-scale drug screen was set up in which genetic alterations and quantitative proteomics were compared with drug sensitivity in a preclinical setting, which revealed that granulocyte macrophage progenitor (GMP)-like AMLs display the greatest sensitivity. Furthermore, we identified that NPM1c/DNMT3Amut AMLs are sensitive, and some NPM1wt AML subtypes without KMT2A-MLLT3 rearrangements benefit from menin-KMT2A inhibition. Genome-wide ChIP-seq studies revealed patient-specific epigenetic alterations upon JNJ-75276617 treatment, uncovering a striking upregulation of MHC class I and class II expression as a consequence of epigenetic changes upon menin-KMT2A inhibition, independent of MEIS1 loss but involving CIITA activation. Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery. https://haematologica.org/article/view/11876 |
| spellingShingle | Shanna M. Hogeling Duy Minh Lê Nikita La Rose Min Chul Kwon Albertus T.J. Wierenga Fiona A.J. van den Heuvel Vincent van den Boom Anna Kuchnio Ulrike Philippar Gerwin Huls Jan Jacob Schuringa Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia Haematologica |
| title | Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia |
| title_full | Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia |
| title_fullStr | Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia |
| title_full_unstemmed | Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia |
| title_short | Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia |
| title_sort | bleximenib the novel menin kmt2a inhibitor jnj 75276617 impairs long term proliferation and immune evasion in acute myeloid leukemia |
| url | https://haematologica.org/article/view/11876 |
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