KMT2A-rearranged leukemia is an aggressive cancer affecting the blood and bone marrow, causing the rapid proliferation of immature white blood cells. Historically, this condition was known as Mixed-Lineage Leukemia (MLL leukemia). The scientific community now uses KMT2A-rearranged leukemia, reflecting the official gene name change. This specific type is defined by a characteristic genetic alteration that drives its aggressive nature.
The Genetic Origin of KMT2A-Rearranged Leukemia
The KMT2A gene, located on chromosome 11, normally regulates other genes within the cell’s nucleus. It encodes a protein that modifies histones through H3K4 methylation, controlling the proliferation and differentiation of blood-forming cells.
The disease begins with a chromosomal translocation, where genetic material is swapped between two chromosomes. This event disrupts the KMT2A gene, fusing it with a segment of another gene. The resulting oncogenic KMT2A fusion protein cannot perform the normal regulatory function.
This fusion protein hijacks the cell’s transcriptional machinery, causing the abnormal activation of genes that should be inactive. It recruits cofactors, such as DOT1L, which drives the expression of target genes like the HOXA and MEIS1 clusters. This inappropriate activation leads to uncontrolled growth and blocks the maturation of white blood cells, resulting in leukemia.
Over 90 different partner genes can fuse with KMT2A, and the specific partner significantly impacts the type of leukemia and prognosis. For instance, KMT2A-AFF1 is often associated with Acute Lymphoblastic Leukemia (ALL), while KMT2A-MLLT3 is more frequently seen in Acute Myeloid Leukemia (AML). Precise molecular identification is necessary because the unique structure of each fusion protein dictates the exact mechanism of oncogenesis.
Distinct Patient Populations and Clinical Manifestations
KMT2A-rearranged leukemia is strongly associated with infant leukemia (diagnosis within the first twelve months of life). This rearrangement is the most common genetic lesion in this age group, accounting for up to 80% of infant acute lymphoblastic leukemia cases. The disease course is aggressive, often presenting with hyperleukocytosis and a high risk of spreading to the central nervous system.
In older children and adults, KMT2A rearrangements occur in 5 to 15% of all acute leukemias, affecting both ALL and AML subtypes. The leukemic cells often show a mixed-lineage phenotype, co-expressing markers of both myeloid and lymphoid cell types, reflecting that the genetic error originates in an early blood cell precursor.
Clinical manifestations relate to the bone marrow’s failure to produce healthy blood cells. Patients may experience fatigue from anemia, fevers from infections due to low white blood cell counts, and easy bruising or bleeding from low platelet counts. The KMT2A rearrangement is the most important factor defining the disease’s poor prognosis.
Identifying the Subtype: Specialized Diagnostic Testing
Confirming KMT2A-rearranged leukemia requires specialized molecular testing, as conventional diagnostics are insufficient. Initial screening often uses Fluorescence In Situ Hybridization (FISH), which employs fluorescent probes to visualize the gene. A KMT2A breakapart FISH probe detects the rearrangement by showing the two ends of the gene separated.
After rearrangement detection, Reverse Transcription Polymerase Chain Reaction (RT-PCR) identifies the exact fusion partner gene by detecting the specific messenger RNA transcript created by the fused genes. This identification is critical for determining prognosis and guiding treatment decisions, as the partner genes provide a precise molecular signature for the cancer.
Next-Generation Sequencing (NGS) is becoming standard for comprehensive molecular profiling in acute leukemias. NGS detects the KMT2A rearrangement and its partner, including cryptic fusions missed by FISH or traditional PCR. This technology allows clinicians to simultaneously search for other genetic alterations that influence risk stratification and therapeutic approach.
Therapeutic Strategies Targeting the KMT2A Fusion
The aggressive nature and high relapse rates of KMT2A-rearranged leukemia necessitate intensive chemotherapy. While chemotherapy aims to eradicate leukemic cells, the genetic driver often causes treatment resistance. For high-risk patients, especially those who relapse, hematopoietic stem cell transplantation (HSCT) remains the primary strategy for achieving a long-term cure.
The unique genetics of this subtype have driven the development of novel, targeted therapies aimed directly at the fusion protein’s mechanism. Since the KMT2A fusion protein is the root cause, targeting it offers a more precise and effective treatment path, leading to new drug classes that interfere with its activity.
Menin Inhibitors
One promising class is Menin inhibitors, which block the interaction between the KMT2A fusion protein and the Menin protein. Menin is a cofactor required by the fusion protein to activate the oncogenic HOXA and MEIS1 genes. Disrupting this interaction causes leukemic cells to stop proliferating and mature into healthy cells, effectively shutting down the cancer’s genetic program.
DOT1L Inhibitors
Another targeted approach involves drugs that inhibit DOT1L, a histone methyltransferase recruited by the KMT2A fusion protein. DOT1L inhibitors, such as pinometostat, reduce the histone methylation that promotes the transcription of leukemia-driving genes. Although single-agent inhibition has shown limited sustained response, its mechanism makes it an attractive partner for combination therapies in clinical trials.