Leukemias with MLL translocations have been the topic of intense interest because of the unusual, biphenotypic immunophenotype of these leukemias, because of the unique clinical presentation of some MLL translocations (infant leukemia and therapy-related leukemia), and because of the large number of different chromosomal loci that partner with MLL in these translocations.
Leukemias carrying MLL rearrangements are quintessential cancers driven by dysregulated epigenetic mechanisms in which fusion proteins containing N-terminal sequences of MLL require few or perhaps no additional mutations to cause human leukemia.
Leukemias with t(4;11)(MLL-AF4) were found to be resistant to the cell death that results from serum deprivation in vitro when compared with B lineage acute leukemias without t(4;11)(MLL-AF4).
MLL can become fused with one of a remarkable panoply of genes from other chromosome locations in individual leukaemias, leading to either acute myeloid or lymphoid tumours (hence the name MLL for mixed lineage leukaemia).
MLL-AF4 is thought to be required in haematopoietic stem cells to elicit leukaemia and may be involved in tumour phenotype specification as it is only found in B-cell tumours in humans.
MLL translocations t(4;11) and t(11;19) characterized extensively hypermethylated leukemias, whereas t(9;11)-positive infant ALL and infant ALL carrying wild-type MLL genes epigenetically resembled normal bone marrow.
MLL1 fusion proteins activate HoxA9 gene expression and cause aggressive leukemias that respond poorly to treatment, but how they recognize and stably bind to HoxA9 is not clearly understood.
MLL1-fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia, which occurs in over 70% infant leukemia patients and often accompanies poor prognosis.
MLL aberrations are detected in around 5-10% of acute myeloid and lymphatic leukemias and an additional 5% of acute myeloid leukemias show a partial internal MLL duplication (PTD).
KMT2A (MLL) rearrangements are observed in various types of pediatric and adult leukemia, but only one adult case report has so far showed KMT2A (MLL)-MLLT1 gene rearrangements in BPDCN.
A different mechanism of oncogene activation in a leukaemia specific chromosomal abnormality is found for CML, where c-abl sequences are fused into the bcr locus, or in the t(4; 11) of acute childhood leukaemia involving the recently identified ALL-1 gene at chromosome 11q23 resulting in a malfunctioning, structurally altered oncogene.
A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO.
A role for EP300 in cancer has been implied by the fact that it is targeted by viral oncoproteins, it is fused to MLL in Leukaemia and two missense sequence alterations in EP300 were identified in epithelial malignancies.
A strong DNase I hypersensitive site (HS) also mapped near exon 9 in four leukemia cell lines, including two in which MLL was rearranged [a t(6;11) and a t(9;11)], and in two lymphoblastoid cell lines with normal MLL.