Acute monocytic leukemia
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Acute monocytic leukemia (AMoL, or AML-M5) is a type of
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...
. In AML-M5 >80% of the leukemic cells are of monocytic lineage. This cancer is characterized by a dominance of
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s in the bone marrow. There is an overproduction of monocytes that the body does not need in the periphery. These overproduced monocytes interfere with normal immune cell production which causes many health complications for the infected individual.


Causes

The pathology of AML involves abnormal proliferation and differentiation of a population of myeloid stem cells. Genetic
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s are identified in the majority of cases. A common genetic mutation identified in these cases are characterized as chromosomal
translocations In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...
where information from one
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
is exchanged to a non-homologous chromosome creating an unusual rearrangement of chromosomes. This translocation is often abbreviated as t(#of one chromosome involved, #of other chromosome involved). M5 is associated with characteristic
chromosomal abnormalities A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where the ...
, often involving
chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
, such as t(9;11), affecting the MLL (KMTA2) locus at 11q23; however MLL translocations are also found in other leukemia subtypes. The t(8;16) translocation in AMoL is associated with hemophagocytosis. These translocations yield the formation of chimeric proteins (RUNX1-RUNX1T1 and PML-RARA, respectively) which disrupt normal myeloid precursor development. Secondary leukaemia, which may include AML-M5, has been associated with exposure to epipodophyllotoxins, such as
etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
. Many cases of AML-M5 are seen to have enhanced phosphorylation of the
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...
protein due to increased induction of cytokines thus increasing cell proliferation and survival. Finally, genetic mutations involved in epigenetic regulation are associated with this leukemia, as they have downstream effects on cell differentiation and proliferation. Excessive cytokine release could be a byproduct of skewed epigenetic regulation.


Diagnosis

In order to fulfill
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 ...
(WHO) criteria for AML-5, a patient must have greater than 20% blasts in the bone marrow, and of these, greater than 80% must be of the monocytic lineage. A further subclassification (M5a versus M5b) is made depending on whether the monocytic cells are predominantly
monoblast Monoblasts are the committed progenitor cells that differentiated from a committed macrophage or dendritic cell precursor (MDP) in the process of hematopoiesis. They are the first developmental stage in the monocyte series leading to a macrophage ...
s (>80%) (acute monoblastic leukemia) or a mixture of monoblasts and promonocytes (<80% blasts). Monoblasts can be distinguished by having a roughly circular
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...
, delicate lacy
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
, and abundant, often basophilic
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. These cells may also have
pseudopod A pseudopod or pseudopodium (plural: pseudopods or pseudopodia) is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filament ...
s. By contrast, promonocytes have a more convoluted nucleus, and their cytoplasm may contain metachromatic granules. Monoblasts are typically MPO-negative and promonocytes are MPO variable. Both monoblasts and promonocytes stain positive for non-specific esterase (NSE), however NSE may often be negative. Immunophenotypically, M5-AML variably express myeloid ( CD13,
CD33 CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. ...
) and monocytic (
CD11b Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as ''macrophage-1 antigen'' (Mac-1) or '' complement receptor 3'' (CR3). ITGAM is also known as CR3A, and cluster of dif ...
,
CD11c CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c . CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alph ...
) markers. Cells may aberrantly express B-cell marker
CD20 B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase ( CD45R+, CD117+) and progressively increasing in concentration until maturity. In humans CD20 is encoded by the ''MS4A1'' gene. This gene ...
and the NK marker
CD56 Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discove ...
. Monoblasts may be positive for
CD34 CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species. CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first descri ...
.


Treatment

AML-M5 is treated with intensive
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
(such as
anthracyclines Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder can ...
) or with
bone marrow transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
. Tyrosine kinase receptor inhibitors are a prominent treatment developed to combat the over activation of cell proliferation proteins induced by AML-5. Inhibiting the STAT3 protein is another useful form of treatment.


References


External links


Image
at hmds.org.uk {{Myeloid malignancy, us=y Acute myeloid leukemia