Alvocidib inhibits IRF4 expression via super‐enhancer suppression and adult T‐cell leukemia/lymphoma cell growth

Abstract

Adult T‐cell leukemia/lymphoma (ATL) is an intractable hematological malignancy with extremely poor prognosis. Recent studies have revealed that super‐enhancers (SE) play important roles in controlling tumor‐specific gene expression and are potential therapeutic targets for neoplastic diseases including ATL. Cyclin‐dependent protein kinase (CDK) 9 is a component of a complex comprising transcription factors (TFs) that bind the SE region. Alvocidib is a CDK9 inhibitor that exerts antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressing SE‐mediated, tumor‐specific gene expression. The present study demonstrated that alvocidib inhibited the proliferation of ATL cell lines and tumor cells from patients with ATL. RNA sequencing (RNA‐Seq) and chromatin immunoprecipitation sequencing (ChIP‐Seq) disclosed that SE regulated IRF4 in the ATL cell lines. Previous studies showed that IRF4 suppression inhibited ATL cell proliferation. Hence, IRF4 is a putative alvocidib target in ATL therapy. The present study revealed that SE‐mediated IRF4 downregulation is a possible mechanism by which alvocidib inhibits ATL proliferation. Alvocidib also suppressed ATL in a mouse xenograft model. Hence, the present work demonstrated that alvocidib has therapeutic efficacy against ATL and partially elucidated its mode of action. It also showed that alvocidib is promising for the clinical treatment of ATL and perhaps other malignancies and neoplasms as well.

CDK9 Inhibitor Induces Apoptosis, Autophagy, and Suppression of Tumor Growth in Adult T-Cell Leukemia/Lymphoma

“…Selective CDK9 inhibitors such as BAY1143752 and alvocidib were effective against ATL in a mouse model study, but it is unknown whether these selective inhibitors induced caspaseindependent cell death. 36,37) We therefore considered the possibility of caspase-independent cell death. Many recent reports suggested an interaction between apoptosis and autophagy, and it is now known that apoptosis suppressor proteins regulate autophagy.…”

Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status

“…Other frequently occurring genes include TP53 (as well as TP73 , a TP53 family SE-associated gene present in adult T-cell leukaemia/lymphoma [ 156 ] and TP63 ), AR [ 157 ], ERG , ETS ( ETV1 , ETV4 [ 158 ], and ETV6 ) and IRF ( IRF1 , IRF2 , IRF4 [ 159 ], and IRF8 ) family members, etc. Notably, TFs, like ERG, androgen receptor (AR), and ETV1, are commonly observed in prostate cancer, while TP53 and MYC are frequently involved in multiple cancer types.…”

“… DNA mutations that form binding sites for new TFs, leading to the formation of SE. TFs increase in expression and overexpression, leading to pathological gene activation Cell growth, survival (viability), proliferation, evasion of immunosurveillance Alvocidib [ 159 ] T-cell acute lymphoblastic leukemia (T-ALL) T-ALL with monoallelic overexpression of TAL1 lacking TAL1d or chromosomal translocations Jurkat, MOLT-3 cells 5.5% (146 paediatric tumours) TAL1 Oncogene, one of the core components MYB, TAL1 complex (RUNX1, GATA3, TAL1, HEB, E2E) Insertion introduces a new binding site for MYB TF, leading to the formation of SE. MYB recruits CBP and RUNX1, GATA-3, and TAL1 itself Establishment of the T-ALL cell state KRAB-dCas9 mediated repression of the E3 enhancer — [ 128 , 315 ] T-ALL 5′TAL1 SE, TAL1-TCRB, TAL1-TCRD, SIL-TAL1 subtypes 443 unselected primary samples from the GRAALL-2003, -2005 and the FRALLE 2000 trials (199 adult; 244 pediatric), T-ALL cell lines ATCC ® , MOLT-4 cells 5% of T-ALL have 5′TAL1 SE mutations TAL1 , TLX1 , TLX3 , CALM-AF10 , MYB , LMO2 TAL1 is a major transcription factor that is dysregulated in more than 50% of T-ALL.…”

Super enhancer lncRNAs: a novel hallmark in cancer

“…AZD4573 could downregulate multiple oncoproteins (MYC, Mcl-1, JunB, PIM3) and deregulate PI3K pathways in diffuse large B-cell lymphoma (DLBCL) [ 103 ]. Alvocidib was another CDK9 inhibitor that exerted antitumor activity by inhibiting IRF4 expression in adult T-cell leukemia/lymphoma via SE suppression [ 105 ].…”