TY - JOUR
T1 - Efficacy of combined CDK9/BET inhibition in preclinical models of MLL-rearranged acute leukemia
AU - McCalmont, Hannah
AU - Li, Ka Leung
AU - Jones, Luke
AU - Toubia, John
AU - Bray, Sarah C.
AU - Casolari, Debora A.
AU - Mayoh, Chelsea
AU - Samaraweera, Saumya E.
AU - Lewis, Ian D.
AU - Prinjha, Rab K.
AU - Smithers, Nicholas
AU - Wang, Shudong
AU - Lock, Richard B.
AU - D'Andrea, Richard J.
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/1/28
Y1 - 2020/1/28
N2 - 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 levels of the short-lived prosurvival protein MCL1,8 a number of CDK9 inhibitors have been selected for clinical 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 superenhancers 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.
AB - 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 levels of the short-lived prosurvival protein MCL1,8 a number of CDK9 inhibitors have been selected for clinical 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 superenhancers 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.
UR - http://www.scopus.com/inward/record.url?scp=85082137816&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2019000586
DO - 10.1182/bloodadvances.2019000586
M3 - Article
C2 - 31971998
AN - SCOPUS:85082137816
SN - 2473-9529
VL - 4
SP - 296
EP - 300
JO - Blood Advances
JF - Blood Advances
IS - 2
ER -