Mixed-phenotype acute leukemia (MPAL) is a group of blood cancers (leukemia) which have combined features ofmyeloid andlymphoid cancers. It is a rare disease, constituting about 2–5% of all leukemia cases.[1] It mostly involve myeloid with either ofT lymphocyte orB lymphocyte progenitors, but in rare cases all the three cell lineages.[2] Knowledge on the cause, clinical features and cellular mechanism is poor, making the treatment and management (prognosis) difficult.[3]
The name "mixed-phenotype acute leukemia" was adopted by theWorld Health Organization in 2008 to include leukemias of ambiguous lineage, acute undifferentiated leukemias and natural killer lymphoblastic leukemias.[4] According to WHO criteria, myeloid lineage is characterised by the presence ofmyeloperoxidase, while B and T lymphoid lineages are indicated by the expression ofCD19 and cytoplasmicCD3.[5]
The fundamental feature of MPAL involves two types oftranlocations that occur in chromosomes 22 and 11. In the former case, there is reciprocal translocation t(9;22)(q34;q11) in chromosome 22, and is known asPhiladelphia chromosome. This chromosome portion contains the gene that codes fortyrosine-protein kinase (BCR-ABL1), which is aproto-oncogene. This results in abnormal tyrosine kinase activity that leads to faulty cell signalling, gene expression and resistance tocell death.[6] In the latter case, there is translocation ofMLL (KMT2A) gene at chromosome 11q23. The aberrant gene produces fusion proteins that act as transcriptional regulators, which overtake the functions of normalMLL andHOX genes. Some proteins inducehistone methylation by activatinghistone methyltransferases.[7] With updated classification, translocations on chromosome 21 and 22 [t(8;21)(q22;q22)], and on 16 and 22 [t(16;16)(p13.1;q22)], as well asinversion on chromosome 16 (p13.1q22) are also included in MPAL.[1]
One of the most unique features of MPAL is that translocations, especially onKMT2A, can change (switch) the nature of the cancer between myeloid and lymphoid.[8] This so-called lineage plasticity is attributed to the unusual clinical conditions (phenotypes) and difficulty in the diagnosis and treatment.[9]
The first possible case of MPAL was reported in 1906 byLeonard Findlay at the Glasgow Royal Infirmary. Describing the diagnosis and post-mortem study, Findlay noted that in addition to the lymphocytes there was "other variety, which is in a much smaller proportion, varies, like the myelocyte, much in shape and size." He reported:
In conclusion, then, there seems no doubt, not only from the condition of the blood during life but also from the pathological findings, that we are dealing here with a hyperplasia of both the myeloid and adenoid tissues.[10]
The definitive cases came into light in 1980 after two separate reports, one fromWestern Infirmary, Glasgow,[11] and the other from William N. Wishard Memorial Hospital (now theSidney & Lois Eskenazi Hospital), Indianapolis.[12] By 1981, the distinction was clearer whenmonoclonal antibodies were used to identify the cancer cells.[13][4] Following three cases fromSt. Jude Children's Research Hospital, Tennessee, the name "acute leukaemia with mixed lymphoid and myeloid phenotype" was introduced.[14] The World Health Organization in itsWHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (2008) adopted the name "mixed-phenotype acute leukemia" to include leukemias of ambiguous lineage, acute undifferentiated leukemias and natural killer lymphoblastic leukemias.[4]