MYC as therapeutic target in leukemia and lymphoma

Abstract

MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

High‐level MYC expression associates with poor survival in patients with acute myeloid leukemia and collaborates with overexpressed p53 in leukemic transformation in patients with myelodysplastic syndrome

“…Early animal studies show overexpression of MYC can induce AML‐like disease, which is enhanced by antiapoptotic BCL family proteins including BCL2, BCLxl, and MCL1 39,40 . MYC rearrangements are rare in AML and MYC amplification is infrequent in AML 41 . Leukemogenic fusion genes such as RUNX1‐RUNX1T1 and PML‐RARα are reported to induce MYC expression 41,42 .…”

“…MYC rearrangements are rare in AML and MYC amplification is infrequent in AML 41 . Leukemogenic fusion genes such as RUNX1‐RUNX1T1 and PML‐RARα are reported to induce MYC expression 41,42 . The prognostic role of MYC overexpression in AML is controversial.…”

Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review)

“…BRD4 has been clinically linked to several oncogenes, such as activating Myc in leukemia and lymphoma ( 121 ). It has also been observed that BRD4 protein and its mRNA levels are abnormally regulated in HNSCC samples, correlated with tumor features such as size, proliferation and advanced disease degree ( 23 ).…”

Role of MYC in B Cell Lymphomagenesis

“…In MYC overexpression, this means that the targets are several signaling pathways required for the neoplastic cell function, which are not essential in normal B cells. Inhibitors of certain proteins in downstream cascades were produced that can cause neoplastic, but not normal, B cell death [107,108]. …”