What Is MLLT1 and Its Role in Leukemia?

The MLLT1 gene, and the protein it produces called ENL, is a subject of interest in cell biology and cancer research. This protein is a component of the cellular machinery that regulates which genes are turned on or off. While it has a function in healthy cells for normal development, its alteration is linked to the development of specific forms of aggressive blood cancers.

The Normal Function of MLLT1 Protein

In a healthy cell, the MLLT1 protein (ENL) is a regulator of gene expression and a component of the super elongation complex (SEC). The SEC helps an enzyme, RNA polymerase II, move efficiently along DNA to create a corresponding RNA molecule in a process called transcription. MLLT1 ensures this process is smooth by preventing the polymerase from pausing, which allows for robust expression of specific genes.

The MLLT1 protein acts as a “reader” of the cell’s epigenetic code. DNA is wound around proteins called histones, and chemical marks on these histones dictate if a gene is active. MLLT1 has a region called a YEATS domain that recognizes and binds to acetylated histone tails. This binding recruits the SEC to active gene sites, promoting their transcription.

This function is important during development and for maintaining the identity of specialized cells. MLLT1 has high expression in bone marrow cells that give rise to B-lymphocytes. It also helps sustain mitochondrial function, which generates energy within the cell. By controlling gene expression, MLLT1 guides the development of these hematopoietic cell lineages.

MLLT1’s Involvement in Leukemia

The link between MLLT1 and cancer is pronounced in acute leukemias, aggressive cancers of the blood and bone marrow. MLLT1 is implicated in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Its role is not from a simple mutation, but a genetic event called a chromosomal translocation, where a piece of one chromosome breaks off and attaches to another.

In these leukemias, the MLLT1 gene on chromosome 19 frequently fuses with the KMT2A gene on chromosome 11. This translocation creates an abnormal hybrid gene, KMT2A-MLLT1. The resulting fusion protein combines parts of both original proteins, leading to a new function that drives leukemia development.

While the KMT2A fusion is most common, MLLT1 can fuse with other gene partners in rarer leukemias. The presence of an MLLT1 translocation is a defining feature of a subset of acute leukemias. These genetic rearrangements are acquired, not inherited, changes within the cells that give rise to the cancer.

Molecular Mechanisms of MLLT1 in Cancer Development

The fusion proteins from MLLT1 translocations drive cancer by corrupting gene regulation. The KMT2A part of the fusion protein binds to specific DNA locations, while the MLLT1 part recruits the transcriptional machinery. This combination hijacks the cell’s gene expression system, leading to the sustained activation of genes that should be turned off.

A set of target genes dysregulated by KMT2A-MLLT1 are the HOX genes. These genes are regulators normally active during embryonic development but are silenced in mature blood cells. The fusion protein turns these HOX genes back on, which blocks the maturation of blood progenitor cells. This locks them in a state of continuous self-renewal and proliferation, a hallmark of leukemia.

This abnormal gene activation is a consequence of the fusion protein’s structure. The MLLT1 portion uses its YEATS domain to bind to acetylated histones, tethering the transcription-activating machinery to the wrong genes. This action turns on pro-cancer genes and alters the cell’s epigenetic landscape, reinforcing a program of uncontrolled cell growth.

Research and Therapeutic Strategies for MLLT1-Related Cancers

The involvement of MLLT1 in driving specific leukemias makes it a focus of research for new cancer therapies. In leukemias with KMT2A-MLLT1 fusions, the translocation is a prognostic marker, often indicating an aggressive disease requiring intensive treatment. This understanding allows for more precise diagnosis and risk assessment.

Developing drugs that target the MLLT1 protein or its fusion product is a primary goal. Researchers are designing small molecules to block the function of the MLLT1 protein’s YEATS domain, preventing it from binding to histones. By disrupting this interaction, these inhibitors aim to shut down the abnormal gene program and halt the growth of leukemia cells.

Progress has been made in creating selective inhibitors of the MLLT1 YEATS domain, such as the experimental compound NVS-MLLT-1. Studies using CRISPR gene-editing have shown that AML cells are dependent on MLLT1 for survival. These findings support targeting MLLT1 as a therapeutic approach, and research continues to refine these strategies for clinical use.