MLL leukemia, also known as KMT2A-rearranged leukemia, is an aggressive type of blood cancer affecting all age groups, though predominantly infants and young children. It is characterized by unique genetic changes that disrupt normal blood cell development.
The MLL Gene and Leukemia
The MLL gene, also known as KMT2A, is located on chromosome 11. In its normal state, it functions as a histone methyltransferase, regulating gene expression and cell development, particularly in blood cell formation. It helps maintain proper expression of genes, including HOX homeobox genes, which are involved in blood cell maturation.
MLL leukemia arises when the MLL gene undergoes specific genetic changes, most commonly translocations. A translocation occurs when a piece of chromosome 11 breaks off and attaches to another chromosome, leading to the fusion of the MLL gene with a different “partner” gene. Over 80 different partner genes have been identified, including AFF1, MLLT3, and MLLT1.
These translocations result in the creation of abnormal fusion proteins. These MLL fusion proteins disrupt the normal function of the MLL gene, leading to uncontrolled proliferation of immature blood cells and a block in their normal development. MLL rearrangements are associated with both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), two main types of rapidly progressing blood cancers. The presence of these fusion proteins characterizes MLL-rearranged leukemias.
Symptoms and Diagnosis
The symptoms of MLL leukemia, like other acute leukemias, often appear suddenly and worsen quickly. Common indicators include persistent fatigue, unexplained fever, easy bruising or bleeding, and paleness due to a low red blood cell count. Individuals may also experience frequent infections because of an impaired immune system. Swollen lymph nodes, an enlarged liver, or an enlarged spleen may also occur.
Diagnosis begins with blood tests, such as a complete blood count (CBC). This test measures the levels of red blood cells, white blood cells, and platelets, often revealing abnormal counts, such as an excess of immature white blood cells (blasts) and a decrease in healthy blood cells. If the CBC suggests leukemia, a bone marrow aspiration and biopsy are performed. This procedure involves taking a small sample of bone marrow to examine the cells under a microscope for the presence and type of leukemia cells.
Genetic testing is performed to confirm MLL leukemia. Cytogenetic analysis examines the chromosomes for translocations or other large-scale abnormalities involving the MLL gene. Molecular testing, such as polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH), identifies the specific MLL gene rearrangements and their fusion partners, which is important for diagnosis and informing treatment strategies.
Current Treatment Strategies
Treatment for MLL leukemia is intensive and involves a combination of approaches tailored to the individual patient. The primary treatment is multi-agent chemotherapy, which aims to destroy leukemia cells and induce remission. Chemotherapy regimens include drugs such as cytarabine and anthracyclines. The specific combination and intensity of chemotherapy vary based on age, the type of leukemia (AML or ALL), and the specific MLL fusion partner.
For many patients, particularly those with high-risk features or those who experience a relapse, hematopoietic stem cell transplantation (HSCT), also known as a bone marrow transplant, may be considered. This procedure involves replacing the patient’s diseased bone marrow with healthy stem cells from a donor. HSCT can offer a chance for long-term remission, especially when performed after initial chemotherapy has achieved a temporary remission.
Emerging targeted therapies are also showing promise for MLL-rearranged leukemias. Menin inhibitors, such as revumenib and ziftomenib, are a new class of drugs that disrupt the interaction between the MLL fusion protein and Menin, a protein essential for the survival and proliferation of MLL-rearranged leukemia cells. These inhibitors work by stopping the expression of genes affected by the altered MLL, leading to leukemia cell differentiation and death. Clinical trials are exploring these and other novel agents, including DOT1L inhibitors, which target another enzyme involved in gene regulation in MLL leukemia.
Prognosis and Future Directions
The prognosis for MLL leukemia can vary, but it is an aggressive form of the disease, particularly in infants. In infants with ALL, the five-year event-free survival rate has ranged from 20% to 40%, which is lower than for those without MLL rearrangements. Factors influencing prognosis include the patient’s age at diagnosis, the specific MLL translocation partner gene, and how well the leukemia responds to initial treatment. Certain fusion partners, like MLL-AF4, are associated with a poorer prognosis compared to others.
Research efforts are focused on improving outcomes for patients with MLL leukemia. Scientists are working to understand the mechanisms by which MLL fusion proteins cause leukemia, which can lead to the development of more specific and effective targeted therapies. The development of drugs like menin inhibitors represents important progress, as they directly target the unique vulnerabilities of MLL-rearranged leukemia cells.
The future directions in treating MLL leukemia involve personalized medicine approaches, where treatment is tailored based on the specific genetic characteristics of an individual’s leukemia. Continued participation in clinical trials is important for patients and families, as these trials offer access to the newest therapies and contribute to advancing scientific understanding and treatment options for this challenging disease.