ABSTRACT
Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.
ABSTRACT
For over 40 years the standard treatment for acute myeloid leukemia (AML) patients has been a combination of chemotherapy consisting of cytarabine and an anthracycline such as daunorubicin. This standard treatment results in complete remission (CR) in the majority of AML patients. However, despite these high CR rates, only 30-40% (<60 years) and 10-20% (>60 years) of patients survive five years after diagnosis. The main cause of this treatment failure is insufficient eradication of a subpopulation of chemotherapy resistant leukemic cells with stem cell-like properties, often referred to as "leukemic stem cells" (LSCs). LSCs co-exist in the bone marrow of the AML patient with residual healthy hematopoietic stem cells (HSCs), which are needed to reconstitute the blood after therapy. To prevent relapse, development of additional therapies targeting LSCs, while sparing HSCs, is essential. As LSCs are rare, heterogeneous and dynamic, these cells are extremely difficult to target by single gene therapies. Modulation of miRNAs and consequently the regulation of hundreds of their targets may be the key to successful elimination of resistant LSCs, either by inducing apoptosis or by sensitizing them for chemotherapy. To address the need for specific targeting of LSCs, miRNA expression patterns in highly enriched HSCs, LSCs, and leukemic progenitors, all derived from the same patients' bone marrow, were determined and differentially expressed miRNAs between LSCs and HSCs and between LSCs and leukemic progenitors were identified. Several of these miRNAs are specifically expressed in LSCs and/or HSCs and associated with AML prognosis and treatment outcome. In this review, we will focus on the expression and function of miRNAs expressed in normal and leukemic stem cells that are residing within the AML bone marrow. Moreover, we will review their possible prospective as specific targets for anti-LSC therapy.
