Mixed-phenotype acute leukemia (MPAL) is a group of blood cancers (

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...

) which have combined features of

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...

and lymphoid cancers. It is a rare disease, constituting about 2–5% of all leukemia cases. It mostly involve myeloid with either of

T lymphocyte A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

B lymphocyte B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

progenitors, but in rare cases all the three cell lineages. Knowledge on the cause, clinical features and cellular mechanism is poor, making the treatment and management (prognosis) difficult. The name "mixed-phenotype acute leukemia" was adopted by the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

in 2008 to include leukemias of ambiguous lineage, acute undifferentiated leukemias and natural killer lymphoblastic leukemias. According to WHO criteria, myeloid lineage is characterised by the presence of

myeloperoxidase Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the ''MPO'' gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry ou ...

, while B and T lymphoid lineages are indicated by the expression of

CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...

and cytoplasmic CD3. __TOC__

Molecular biology

The fundamental feature of MPAL involves two types of tranlocations 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 as

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

. This chromosome portion contains the gene that codes for tyrosine-protein kinase (BCR-ABL1), which is a

proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. This results in abnormal tyrosine kinase activity that leads to faulty cell signalling, gene expression and resistance to

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

. In the latter case, there is translocation of ''MLL'' (''

KMT2A Histone-lysine ''N''-methyltransferase 2A also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), or zinc finger protein HRX (HRX) is an enzyme that in humans is encoded by the ''KMT2A'' gene. ML ...

'') gene at chromosome 11q23. The aberrant gene produces fusion proteins that act as transcriptional regulators, which overtake the functions of normal ''MLL'' and ''HOX'' genes. Some proteins induce

histone methylation Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrea ...

by activating

histone methyltransferases Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues ...

. With updated classification, translocations on chromosome 21 and 22 (8;21)(q22;q22) and on 16 and 22 (16;16)(p13.1;q22) as well as

inversion Inversion or inversions may refer to: Arts * , a French gay magazine (1924/1925) * ''Inversion'' (artwork), a 2005 temporary sculpture in Houston, Texas * Inversion (music), a term with various meanings in music theory and musical set theory * ...

on chromosome 16 (p13.1q22) are also included in MPAL. One of the most unique features of MPAL is that translocations, especially on ''KMT2A,'' can change (switch) the nature of the cancer between myeloid and lymphoid. This so-called lineage plasticity is attributed to the unusual clinical conditions (phenotypes) and difficulty in the diagnosis and treatment.

History

The first possible case of MPAL was reported in 1906 by

Leonard Findlay Leonard Findlay (5 February 1878, in Glasgow – 14 June 1947) was the pediatrician who was the first Leonard Gow Lecturer on the Medical Diseases of Infancy and Childhood. Findlay was also the first person to hold the Samson Gemmell Chair of Ch ...

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.

The definitive cases came into light in 1980 after two separate reports, one from

Western Infirmary The Western Infirmary was a teaching hospital situated in the West End of Glasgow, Scotland, that was managed by NHS Greater Glasgow and Clyde. It was opened in 1874 and closed in 2015. History After the University of Glasgow moved from the city ...

, Glasgow, and the other from William N. Wishard Memorial Hospital (now the

Sidney & Lois Eskenazi Hospital The Sidney & Lois Eskenazi Hospital is a public hospital located in Indianapolis, Indiana. The hospital is the flagship medical center for Eskenazi Health, founded in 1859 as Indiana's oldest public healthcare system. The hospital is operated by H ...

), Indianapolis. By 1981, the distinction was clearer when

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

were used to identify the cancer cells. Following three cases from St. Jude Children's Research Hospital, Tennessee, the name "acute leukaemia with mixed lymphoid and myeloid phenotype" was introduced. The World Health Organization in its ''WHO 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.

References

{{Reflist Acute leukemia Hematologic malignant neoplasms