Acute Leukaemia: Mixed Lineage Leukaemia
MLL represents only 3% to 5% of acute leukaemias occurring in patients of all ages. Of these, two patient populations comprise the majority of cases: patients younger than 1 year of age at diagnosis (primarily acute lymphoblastic leukaemia) and young- to middle-aged adults (primarily acute myeloid leukaemia). A much rarer subgroup of patients with KMT2A rearrangements develop leukaemia due to prior treatment with certain chemotherapeutic agents and are referred to as therapy related leukaemia.
KMT2A translocation as a subgroup of acute leukaemia which is associated with certain phenotypic features that sets it apart from other classes of leukaemia. KMT2A-translocated (KMT2A-t) acute leukaemia, particularly in infants, are more likely to present with hyperleukocytosis, in KMT2A-t B cell acute lymphocytic leukaemia (B-ALL) central nervous system (CNS) involvement is common. Other symptoms can include fever, bruising or bleeding, pale skin, appetite loss, fatigue, hepatosplenomegaly and weight loss, these symptoms overlap with many other acute leukaemia. In cases of KMT2A-t B-cell acute lymphoblastic leukaemia (B-ALL), the blasts are typically of the pro-B phenotype and lack expression of CD10 (common ALL antigen) and frequently show co-expression of myeloid markers resulting in a bi-phenotypic leukaemia, thus aiding in the diagnosis of MLL.
In general, outcomes for all of these patients remain poor when compared to patients with non-KMT2A-t leukaemia. This variation of leukaemia is known to be found more commonly in paediatric patients, when the onset occurs within the first year of life and the patient is subjected to a high-risk protocol. As this leukaemia is so aggressive and has an unfavourable prognosis, the accurate detection of MLL is crucial. Currently, methods used to detect MLL include conventional cytogenetics, fluorescent in situ hybridization (FISH), reverse transcription PCR (RT-PCR), as well as long distance inverse PCR. These methods are known to be costly, as it requires specialized skills and expensive reagents. Generally more than one of these tests need to be performed as KMT2A-translocations are commonly cryptic on cytogenetics yet cytogenetics is still the gold standard as it allows you to detect whether the leukaemia has progressed and secondary abnormalities have occurred. A rapid and cost effective technique would be useful. Studies have shown that NG2 immunophenotyping is a reliable tool for the detection of MLL.
According to Winters and Bernt (2017) there have been more than 80 different partner genes in KMT2A fusions, although the majority of leukaemia result from KMT2A fusions with one of six common partner genes: AF4 found on chromosome 4 at band 4q21, AF6 found on chromosome 6 at band 6q27, AF9 found on chromosome 9 at band 9p21, ELL found on chromosome 19 at band 19p13. 1 and ENL (MLLT1) on chromosome 19 at band 19p13. 3. In B-ALL, the most frequent fusion partner is the AF4 protein (ALL-1 fused gene), which will fuse with the KMT2A gene which results in t(4;11)(q21;q23). According to Winters and Bernt (2017) AF4 positive B-ALL is responsible for about fifty percent of KMT2A rearrangements in infant B-ALL cases below the age of 6 months. In older children and adults, the incidence accounts for less than 5% of B-ALL cases. Less common fusion partners for KMT2A in B-ALL would be gene eleven-nineteen leukaemia gene (ENL) on chromosome 19 at band p13. 3 as well as ALL-1 fused gene from chromosome 9 (AF9) on chromosome 9 at band p21-22. If figure 1 and 2 are compared, it is observed that the t(9;11) is a lot more difficult to detect than the t(11;19) thus highlighting the cryptic nature of this translocation. B-ALL blasts with a KMT2A translocation immunophenotypically express CD9, CD34, and TDT positive and frequently express myeloid associated antigens CD15 and/or CD65 demonstrating a bi-phenotypic leukaemia.
In AML, alterations in chromosome band 11q23 are predominantly found in the monocytic and myelomonocytic categories. Expression of monocyte-associated markers CD4, CD14, CD11b, CD64, and CD56 are common, as well as frequent expression of B-cell markers has been reported.
