MYB refers to a family of genes that provide the instructions for making a group of proteins known as transcription factors. The most studied member of this family is c-Myb, which is classified as a proto-oncogene—a normal gene that has the potential to become a cancer-causing gene. In a healthy state, these proteins are involved in controlling a wide range of cellular activities, including growth and the rate at which cells divide.
The Normal Role of the MYB Protein
A primary responsibility of the MYB protein is in the process of hematopoiesis, which is the formation and development of all types of blood cells from a common hematopoietic stem cell. During this process, MYB guides immature progenitor cells along specific pathways, influencing their decision to become mature red blood cells, white blood cells, or platelets. This ensures the body maintains a healthy and balanced supply of different blood cell lineages.
The protein’s influence is particularly notable in the self-renewal of hematopoietic stem cells and the proliferation of progenitor cells. It helps maintain a pool of undifferentiated cells while also directing their maturation into specialized cells needed to replenish the blood and immune system. This dual role in promoting proliferation while guiding differentiation highlights its precise and context-dependent function in normal tissue maintenance.
Beyond blood cell formation, MYB is also involved in the normal development and maintenance of other tissues, including the epithelial lining of the colon. In colonic crypts, which are glands found in the lining of the colon, MYB helps regulate the balance between cell division and differentiation. This controlled process is necessary for the constant renewal of the intestinal lining, ensuring its integrity and proper function.
How MYB Contributes to Cancer
The transition of the MYB gene from a normal proto-oncogene to a cancer-promoting oncogene occurs through several genetic alterations. These changes disrupt its regulated function, leading to uncontrolled cell growth and survival. One common mechanism is overexpression, where cells produce an excessive amount of the MYB protein. This can happen due to gene amplification, where the cell makes multiple copies of the MYB gene, or through failures in the molecular machinery that keeps its expression in check.
Another mechanism is chromosomal translocation. In this event, a piece of the chromosome containing the MYB gene breaks off and fuses with another gene on a different chromosome. This joining creates an abnormal fusion gene, which then produces a hybrid protein with new, unregulated functions. This resulting fusion protein can drive cancer development by activating growth pathways that are normally dormant.
Mutations within the MYB gene itself can also lead to its oncogenic activity. These changes in the DNA sequence can alter the structure of the MYB protein, making it hyperactive or more stable than its normal counterpart. A hyperactive protein may continuously signal for cell division, while an overly stable protein can resist the natural cellular processes that would normally break it down, allowing it to accumulate to high levels and persistently drive cell proliferation.
Cancers Associated with MYB Alterations
Alterations in the MYB gene are linked to several types of human cancers, with some malignancies showing a particularly high frequency of these changes. One well-defined example is adenoid cystic carcinoma (ACC), a rare cancer that arises in the salivary glands. In many ACC cases, a chromosomal translocation fuses the MYB gene with another gene, most commonly NFIB. This MYB-NFIB fusion is a defining characteristic and primary driver of tumor growth.
MYB alterations are also frequently implicated in various forms of leukemia, which are cancers of the blood-forming tissues. In T-cell acute lymphoblastic leukemia (T-ALL), for instance, duplications or translocations involving the MYB gene lead to its overexpression, promoting the survival and proliferation of leukemia cells. In acute myeloid leukemia (AML), cancer cells often show a strong dependence on high levels of MYB for their growth and survival, a phenomenon described as “MYB addiction.”
Beyond hematological malignancies and ACC, aberrant MYB expression has been observed in several solid tumors. Its involvement has been noted in certain cases of colon and breast cancer. In some types of breast cancer, the estrogen receptor can drive the expression of MYB, linking it to hormone-driven tumor growth. In colon cancer, high levels of MYB expression are often associated with a poor prognosis and are thought to contribute to the self-renewal properties of cancer stem cells.
Therapeutic Strategies Targeting MYB
The MYB protein was long considered an “undruggable” target for cancer therapy. As a transcription factor, it functions by binding to DNA within the cell nucleus, and it lacks the well-defined pockets on its surface that small-molecule drugs are designed to fit into. This structural characteristic makes it difficult to develop inhibitors that can directly block its cancer-promoting activity.
Researchers are exploring new strategies to overcome this challenge. One approach focuses on disrupting the interaction between MYB and its partner proteins. MYB does not work in isolation; it collaborates with other proteins, such as p300, to activate its target genes. Scientists are developing small molecules designed to block the specific site where these two proteins connect, thereby preventing MYB from carrying out its function without having to bind to MYB directly.
Another therapeutic angle aims to interfere with the production of the MYB protein itself. This can be achieved using technologies that target the messenger RNA (mRNA) that carries the genetic instructions from the MYB gene to the cell’s protein-making machinery. By degrading the MYB mRNA, these approaches can lower the amount of the harmful protein in cancer cells, reducing their ability to proliferate and survive.
These developing strategies represent a shift away from direct inhibition toward a more nuanced understanding of how to neutralize a difficult-to-target protein. While in the research and development phase, these methods offer potential new avenues for treating cancers that are dependent on MYB. The focus remains on finding a way to selectively shut down its activity in cancer cells while sparing the normal cells that also rely on its function.