Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Abstract

Key Points• Inhibition of Myb activity by a small molecule blocks proliferation of AML cells and prolongs survival of mice in an in vivo AML model.The transcription factor Myb plays a key role in the hematopoietic system and has been implicated in the development of leukemia and other human cancers. Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. However, because of a lack of suitable inhibitors, the feasibility of therapeutic approaches based on Myb inhibition has not been explored. We have identified the triterpenoid Celastrol as a potent low-molecular-weight inhibitor of the interaction of Myb with its cooperation partner p300. We demonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia (AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrol prolongs the survival of mice in a model of an aggressive AML. Overall, our work demonstrates the therapeutic potential of a small molecule inhibitor of the Myb/p300 interaction for the treatment of AML and provides a starting point for the further development of Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors driven by deregulated Myb. (Blood. 2016;127(9):1173-1182 Introduction Myb, the protein encoded by the MYB proto-oncogene, is now recognized as an attractive therapeutic target for the treatment of leukemia and potentially for other human tumors.1 Myb was originally discovered as the cellular progenitor of the transforming v-Myb transduced by avian myeloblastosis virus. 2,3 Myb is expressed in the hematopoietic progenitor cells, where it acts as a transcription factor to control genes important for lineage determination, cell proliferation, and differentiation. 4,5 The analysis of Myb null and conditional knockout mice and of mice bearing hypomorphic Myb alleles has demonstrated that Myb is essential for most hematopoietic lineages. [6][7][8][9][10][11] Myb is also expressed in several nonhematopoietic tissues, 12 such as the colonic crypts, where it controls the proliferation and differentiation of the intestinal stem cells. 13 Recent work has shown that deregulated Myb plays critical roles in leukemias and other types of cancer. Recurrent translocations and duplications of the Myb locus occur in acute lymphoblastic leukemia of young children. [14][15][16] In addition, genomic rearrangements of Myb have been reported in acute myelomonocytic and basophilic leukemia. [17][18][19] Although such rearrangements are relatively rare, they indicate that aberrant Myb expression contributes to the development of leukemia. Importantly, it has now been realized that Myb also plays essential roles in leukemias caused by genetic lesions of other genes, such as leukemias driven by human acute myeloid leukemia (AML) oncogenes. [20][21][22][23][24][25][26] High expression of Myb is a common characteristic of these leukemias and is essential for maintenance of the leukemic cells. This was initially observed in studies with Myb ant...

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

“…To test the performance of the cell system (referred to as Hek-Myb-Luc), we treated the cells with Celastrol, a previously identified MYB inhibitor 25 . As shown in Fig.…”

“…Several recent reports have demonstrated that MYB is a druggable target whose inhibition might permit new therapeutic strategies for the treatment of AML 25,26,49–51 . To facilitate the identification of such compounds we have developed a reporter cell line that is based on the doxycycline-inducible expression of an activated version of human MYB acting upon a stably integrated MYB-dependent luciferase reporter.…”

MYB deregulation from a EWSR1-MYB fusion at leukemic evolution of a JAK2 V617F positive primary myelofibrosis

“…High level of MYB is common in AML associated with BCR-ABL1, RUNX1-RUNX1T1, MYST3-CREBBP , or MLL- rearrangements [11, 12, 24]. Chromosomal aberrations placing MYB under the promoter of a partner gene, such as TCRB-MYB in T-cell ALL [14, 25] or in close proximity of super-enhancer regions, such as MYB-NFIB in adenoid cystic carcinoma [26], caused MYB over-expression.…”

“…High MYB level confers self-renewal properties on leukemic cells and blocks differentiation, thus it has been regarded as a putative therapeutic target [11, 12]. Indeed, in vitro and in vivo studies showed that a slight MYB drop is enough to block leukemic cell proliferation without affecting normal haematopoiesis [28].…”

Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer

“…In RB cells, it was found to inhibit the NF-κB pathway. In acute myeloid leukemia cells, it was found to inhibit MYB activity by blocking its interaction with p300, a transcriptional cofactor [113]. …”