Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia
| Autor: | John Toubia, Hannah McCalmont, Debora A. Casolari, Chelsea Mayoh, Saumya E. Samaraweera, Richard J D'Andrea, Sarah C Bray, Ka Leung Li, Ian D. Lewis, Rab K. Prinjha, Nicholas Smithers, Luke Jones, Shudong Wang, Richard B. Lock |
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| Přispěvatelé: | McCalmont, Hannah, Li, Ka Leung, Jones, Luke, Toubia, John, Bray, Sarah C, Casolari, Debora A, Mayoh, Chelsea, Samaraweera, Saumya E, Lewis, Ian D, Prinjha, Rab K, Smithers, Nicholas, Wang, Shudong, Lock, Richard B |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
BRD4 cyclin-dependent kinase inhibitors Mice 03 medical and health sciences 0302 clinical medicine stimulus report hemic and lymphatic diseases medicine Animals Humans lymphoid neoplasia P-TEFb neoplasms Acute leukemia biology leukemia acute Myeloid leukemia Hematology medicine.disease Cyclin-Dependent Kinase 9 Stimulus Report Infant Acute Lymphoblastic Leukemia Leukemia Myeloid Acute Leukemia 030104 developmental biology KMT2A 030220 oncology & carcinogenesis biology.protein Cancer research Myeloid-Lymphoid Leukemia Protein Female myeloid neoplasia |
| Zdroj: | Blood Advances. 4:296-300 |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | Chromosomal rearrangements of the lysine methyltransferase 2A (KMT2A or MLL) gene are observed in ;10% of all acute leukemias, with particularly high frequency (;80%) in infant acute lymphoblastic leukemia (ALL),1 where, despite aggressive chemotherapy, patients still experience poor outcome and long-term side effects.2 Mixed lineage leukemia (MLL) rearrangements (MLL-r)also indicate particularly poor outcomes for patients with acute myeloid leukemia (AML).3 Mechanistically, MLL-r frequently generates fusion proteins involving partners that function in the super elongation complex,4 the result of which is aberrant recruitment to MLL target genes of the positive transcription elongation factor b (PTEFb), composed of cyclin-dependent kinase 9 (CDK9)as the catalytic subunit.5 CDK9 positively regulates transcription elongation through phosphorylation of serine 2 of RNA polymerase II (RNAPII).6 Given the central role of CDK9 in the leukemic MLL-r gene-expression program,7 and the well-described ability of CDK9 inhibitors to reduce levelsof the short-lived prosurvival protein MCL1,8 a number of CDK9 inhibitors have been selected forclinical trials focusing on acute leukemias, including those with MLL-r.8,9 In MLL-r leukemia, the bromodomain and extraterminal (BET) family member bromodomain-containing 4 (BRD4)10 acts to recruit PTEFb to super enhancers and together with CDK9 drives increased expression of many oncogenes including MYC.11,12 The roles of CDK9 and BRD4 in MLL-r leukemias present a strong case for testing inhibitors of these proteins in combination as a potential treatment of MLL-r acute leukemias. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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