KMT2A Acute Myeloid Leukemia is an aggressive subtype of acute myeloid leukemia (AML) that arises from genetic alterations in the KMT2A gene. These changes lead to the production of abnormal proteins, which disrupt normal blood cell development in the bone marrow. Recognizing this particular subtype is important because it often has different disease characteristics and treatment responses compared to other forms of AML. This article will explore the underlying biology of KMT2A AML, its typical presentation, diagnosis, and treatment strategies employed.
Understanding KMT2A and Acute Myeloid Leukemia
The KMT2A gene, previously known as MLL, is located on chromosome 11 at position 11q23.3. This gene plays a role in early development and the formation of blood cells. KMT2A acts as a transcriptional coactivator, influencing the expression of other genes, particularly those involved in cell growth and differentiation, by modifying histone H3 proteins.
Acute myeloid leukemia is a cancer that originates in the bone marrow, the soft, spongy tissue inside bones where blood cells are made. In AML, immature white blood cells, known as myeloblasts or leukemic blasts, are overproduced. These abnormal cells accumulate and crowd out healthy blood-forming cells, leading to a shortage of normal red blood cells, white blood cells, and platelets.
KMT2A and AML are linked when the KMT2A gene undergoes rearrangements or translocations. These genetic changes involve a segment of the KMT2A gene fuses with another gene, creating an abnormal fusion gene. Over 100 KMT2A fusion partners have been identified, though fewer are common in AML.
These fusion genes produce chimeric proteins that interfere with normal gene expression. This disrupts normal gene expression, leading to uncontrolled growth and survival of immature blood cells that fail to mature. These altered proteins often activate genes like HOXA and MEIS1, which promote leukemia development.
Clinical Presentation and Diagnosis
KMT2A AML often presents with symptoms similar to other types of acute myeloid leukemia. Common signs include persistent fatigue, paleness, and shortness of breath due to anemia (low red blood cell count). Patients may also experience frequent infections because of a lack of functional white blood cells, as well as easy bruising or bleeding due to low platelet counts.
This subtype of AML can also manifest with aggressive features like hyperleukocytosis (high white blood cell count) or extramedullary involvement, where leukemia cells spread outside the bone marrow to organs such as the spleen, liver, or lymph nodes. KMT2A rearrangements are common in infants and young children, accounting for a high percentage of acute leukemias in this age group. They also occur in adults, affecting 5-15% of adult AML cases.
Identifying KMT2A rearrangements is important as it indicates a distinct prognosis. It is associated with an unfavorable outcome, often resistant to standard chemotherapy and having higher relapse rates. Confirming KMT2A rearrangements guides treatment decisions and risk stratification.
Diagnosis of KMT2A rearrangements relies on genetic testing methods. Conventional cytogenetics, such as karyotyping, can detect larger chromosomal abnormalities but may miss smaller or “cryptic” KMT2A translocations. Fluorescence in situ hybridization (FISH) uses DNA probes to visualize gene rearrangements, including KMT2A fusions. More sensitive molecular tests, such as reverse transcription polymerase chain reaction (RT-PCR) and next-generation sequencing (NGS), are often employed to confirm KMT2A fusion genes and their partner genes.
Treatment Strategies
Treatment for KMT2A AML begins with intensive chemotherapy regimens. These regimens aim to eliminate leukemia cells and achieve remission, a significant reduction or disappearance of leukemia cells. However, KMT2A-rearranged AML is often resistant to conventional chemotherapy, leading to lower remission rates and a higher likelihood of relapse.
The development of targeted therapies, particularly menin inhibitors, is a significant advancement for patients with KMT2A-rearranged AML. Menin is a protein that interacts with abnormal KMT2A fusion proteins. This interaction is necessary for leukemia cell growth and survival. Menin inhibitors work by disrupting this interaction, blocking signaling pathways that drive KMT2A-rearranged leukemia cell growth. This leads to differentiation and programmed cell death of leukemic cells, offering a promising approach to overcome traditional chemotherapy limitations.
Hematopoietic stem cell transplantation (HSCT) is often considered a curative option for KMT2A AML, especially for patients in remission after initial treatment. HSCT involves replacing diseased bone marrow with healthy donor stem cells. This procedure can improve long-term survival rates, especially when performed in first complete remission with no detectable residual disease.
Treatment decisions for KMT2A AML are individualized, considering factors beyond the KMT2A rearrangement. Age, overall health, specific KMT2A fusion partner, and response to initial therapies all influence the treatment plan. The goal is to select the most effective strategy for durable remission and improved long-term outcomes.