Acute megakaryoblastic leukemia (AMKL) is life-threatening
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 ...
in which
malignant
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
megakaryoblast
A megakaryoblast is a precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis. It is the beginning of the thrombocytic series.
Development
The megakaryoblast derives from a CFU-Meg colony unit of pluripot ...
s proliferate abnormally and injure various tissues.
Megakaryoblast
A megakaryoblast is a precursor cell to a promegakaryocyte, which in turn becomes a megakaryocyte during haematopoiesis. It is the beginning of the thrombocytic series.
Development
The megakaryoblast derives from a CFU-Meg colony unit of pluripot ...
s are the most immature precursor cells in a
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
-forming lineage; they mature to
promegakaryocyte
A promegakaryocyte is a precursor cell for a megakaryocyte. It arises from a megakaryoblast, into a promegakaryocyte and then into a megakaryocyte, which will eventually break off and become a platelet.
The developmental stages of the megakaryoc ...
s and, ultimately,
megakaryocyte
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In ...
s which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.
AMKL is commonly regarded as a subtype 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 ...
(AML). More formally, it is classified under the AML-
M7 category of the
French-American-British classification and 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 ...
of 2016 in the AML-Not Otherwise Specified subcategory.
Acute megakaryoblastic leukemia falls into three distinct groups which differ in underlying causes, ages of presentation, responses to therapy, and prognoses. These groups are: AMKL occurring in young children with
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
, i.e. DS-AMKL; AMKL occurring in children who do not have Down syndrome, i.e. non-DS-AMKL (also termed pediatric acute megakaryoblastic leukemia or pediatric AMKL); and AMKL occurring in non-DS adults, i.e. adult-AMKL.
AMKL, while rare, is the most common form of AML in DS-AMKL, occurring ~500-fold more commonly in Down syndrome children than in children without Down syndrome; non-DS-AMKL and adult-AMLK are rare, accounting for <1% of all individuals diagnosed as in the AML-M7 category of leukemia.
DS-AMKL
Pathophysiology
Individuals with Down syndrome almost always have three instead of the normal two copies of
chromosome 21
Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. M ...
. The extra copies of key chromosome 21 genes underlie their increased susceptibility to AMKL by promoting the development of a certain type of inactivating mutation in the ''GATA1'' gene.
The ''GATA1'' gene resides on the
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...
and codes for two
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
, GATA1 and a shorter version, GATA1-S.
GATA1 and GATA1-S contribute to regulating the expression of genes that control the maturation of megakaryoblasts to promegakaryocytes, megakaryocytes, and platelets as well as the maturation of
erythroblast
A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of t ...
s to
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s. GATA1-S appears less active than GATA1 in controlling some of the genes that promote megakaryoblast maturation but more active than GATA1 in stimulating megakaryoblast proliferation.
Various ''GATA1'' mutations that cause this gene to make GATA1-S but unable to make GATA1 result in the excessive proliferation of platelet precursor cells, reductions in the levels of circulating blood platelets, mild reductions in the levels of circulating red blood cells, and the development of
transient myeloproliferative disease
Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological c ...
(TMD).
TMD is a disorder involving the excessive proliferation of non-malignant megakaryoblasts and descendent cells due to the cited truncating mutations in the ''GATA1'' gene. TMD is a necessary predecessor to DS-AMKL.
Down syndrome fetuses
and neonates
with one of the cited types of ''GATA1'' truncating mutations are in rare cases asymptomatic (i.e. silent TMD) but more commonly exhibit ''in utero'' or during the first months of live accumulations of immature megakaryoblasts in, and sometimes life-threatening injury to, the fetal blood-forming organ, the liver, and other tissues. While fatal in up to 20% of cases, ~80 of infants with TMD fully recover from the diseases within 4 months.
However, ~10% of individuals with a history of symptomatic or silent TMD develop DS-AMKL within 4 years.
During this interval, these individuals may acquire
somatic mutations in those of their megakaryoblasts that bear the original truncating GATA1 mutation. These newly acquired mutations appear to result from the interactions of ''GATAT1'' truncating mutations with excessive copies of chromosome 21 genes. The genes with these mutations include ''
TP53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
,
FLT3
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the ''FLT3'' gene. FLT3 is a cyto ...
,
ERG
The erg is a unit of energy equal to 10−7joules (100 nJ). It originated in the Centimetre–gram–second system of units (CGS). It has the symbol ''erg''. The erg is not an SI unit. Its name is derived from (), a Greek word meaning 'work' o ...
,
DYRK1A
Dual specificity tyrosine-phosphorylation-regulated kinase 1A is an enzyme that in humans is encoded by the ''DYRK1A'' gene. Alternative splicing of this gene generates several transcript variants differing from each other either in the Five prime ...
,
CHAF1B,
HLCS
Holocarboxylase synthetase (biotin—(propionyl-Coenzyme A-carboxylase (ATP-hydrolysing)) ligase)), also known as protein—biotin ligase, is a family of enzymes ({{{EnzExplorer, 6.3.4.10). This enzyme is important for the effective use of bi ...
,
RUNX1
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the ''RUNX1'' gene.
RUNX1 is a transcription factor that re ...
, MIR125B2'' (which is the gene for
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
MiR125B2
CTCF
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the ''CTCF'' gene. CTCF is involved in many cellular processes, including transcriptional regulatio ...
,
''
STAG2
Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the ''STAG2'' gene. SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is form ...
,
RAD21,
SMC3
Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesi ...
,
SMC1A
Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the ''SMC1A'' gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. ...
,
NIPBL
Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the ''NIPBL'' gene. NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozy ...
,
SUZ12
Polycomb protein SUZ12 is a protein that in humans is encoded by the ''SUZ12'' gene.
Function
This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recomb ...
,
PRC2
PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 ( Polycomb Repressive Complex 1).
This complex has histone methyltransferase activity and ...
,
JAK1
JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...
,
JAK2
Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF rece ...
,
JAK3,
MPL,
KRAS
''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cel ...
,
NRAS'', and ''
SH2B3
SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the ''SH2B3'' gene on chromosome 12.
SH2B adapter protein 3 is a protein that in humans is encoded by the SH2B3 gene on chrom ...
''.
At least one but probably several of these mutations, whether occurring in individuals with silent or symptomatic TMD, are presumed responsible for or to contribute to the development of DS-AMKL.
Rare cases of transient myeloproliferative disease and DS-AMKL occur in individuals who do not have Down syndrome.
These individuals usually have a history of TMD and invariably have megakaryoblasts which bear extra copies of key chromosome 21 genes, truncating mutations in ''GATA1'', and somatic mutations in one or more of the genes listed in the previous section. These individuals have extra copies of only a portion of the genes on chromosome 21. This duplication of only some chromosome 21 genes results from: a)
Robertsonian translocations, wherein part of chromosome 21 is duplicated on another chromosome; b) partial trisomy 21, wherein only part of chromosome 21 is duplicated); c) an
isochromosome, wherein chromosome 21 contains two long but no short arms); or d) duplications, wherein extra chromosome 21 genes are on this or other chromosomes.
AMKL occurring in these individuals is classified as DS-AMKL.
Presentation
DS-AMKL most often presents in children 1–2 years old but almost always less than 4 years old who have a history of TMD. Given this history, these children are usually followed-up medically with
complete blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and pl ...
tests. and therefore often present with elevated blood levels of abnormally appearing platelets and platelet precursor cells, particularly megakaryoblasts, and reduced blood levels of red blood cells. DS-AMKL usually progresses slowly with affected children gradually developing increasingly more severe changes in their blood counts as well as slowly developing symptoms of these developments such as fatigue and shortness of breath due to anemia.
In cases of advanced disease, individuals with DS-AMKL may present with
signs and symptoms that are more typical of acute myeloid leukemic diseases such as liver enlargement, spleen enlargement,
leukemia cutis (i.e. skin nodules caused by leukemic infiltrates), or
leukostasis
Leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency most commonly seen in patients with acute myeloid leukemia. It is characterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion. Th ...
(i.e. an emergency situation in which excessive elevations in circulating
blast
Blast or The Blast may refer to:
*Explosion, a rapid increase in volume and release of energy in an extreme manner
*Detonation, an exothermic front accelerating through a medium that eventually drives a shock front
Film
* ''Blast'' (1997 film), ...
(i.e. early precursor) cells plug the
microcirculation
The microcirculation is the circulation of the blood in the smallest blood vessels, the microvessels of the microvasculature present within organ tissues. The microvessels include terminal arterioles, metarterioles, capillaries, and venules. ...
to cause life-threatening heart, lung, and neurological dysfunctions).
Diagnosis
The diagnosis of DS-AMKL in young children is indicated by: a history of TMD; findings of increased presence of blast cells (e.g. ≥20% of nucleated cells) that have the megakaryoblast phenotype in blood and/or
bone marrow as defined by the morphology of these cells in blood or bone marrow smears; failure to obtain a bone marrow aspirate because of marrow
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
; and
immunophenotyping analyses of platelet precursor cells lineage as determined by
flow cytometry and
immunohistochemistry.
Malignant megakaryoblasts are usually medium-sized to large cells with a high
nuclear-cytoplasmic ratio. Nuclear
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 ...
is dense and homogeneous. There is scanty, variable
basophilic
Basophilic is a technical term used by pathologists. It describes the appearance of cells, tissues and cellular structures as seen through the microscope after a histological section has been stained with a basic dye. The most common such dye i ...
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. ...
which may be excessively
vacuolated. An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present. Megakaryoblasts lack
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 ...
(MPO) activity and stain negatively with
Sudan Black B. They are alpha naphthyl butyrate esterase negative and manifest variable alpha naphthyl acetate esterase activity usually in scattered clumps or granules in the cytoplasm.
PAS diastase stain
Periodic acid–Schiff–diastase (PAS-D, PAS diastase) stain is a periodic acid–Schiff (PAS) stain used in combination with diastase, an enzyme that breaks down glycogen. PAS-D is a stain often used by pathologists as an ancillary study in ma ...
ing varies from negative to focal or granular positivity to strongly positive.
Immunochemical analyses, often conducted by flow cytometry, of the surface antigens on leukemic blast cells are positive for
CD41
Integrin alpha-IIb is a protein that in humans is encoded by the ''ITGA2B'' gene. ITGA2B, also known as CD41, encodes integrin alpha chain 2b. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alp ...
,
CD42b,
CD51, and
Von Willebrand factor
Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytope ...
in AMKL but not leukemia involving non-platelet malignant cells.
Where indicated and available, the diagnosis of DS-AMKL is further supported by; immunophenotyping analysis using
monoclonal antibody
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 ...
directed against megakaryocyte restricted antigen (
CD41
Integrin alpha-IIb is a protein that in humans is encoded by the ''ITGA2B'' gene. ITGA2B, also known as CD41, encodes integrin alpha chain 2b. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alp ...
and
CD61
Integrin beta-3 (β3) or CD61 is a protein that in humans is encoded by the ''ITGB3'' gene. CD61 is a cluster of differentiation found on thrombocytes.
Structure and function
The ITGB3 protein product is the integrin beta chain beta 3. Integrins ...
)
and
DNA sequencing to detect ''GATA1'' mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors.
Treatment
The
chemotherapy regimens
A chemotherapy regimen is a regimen for chemotherapy, defining the drugs to be used, their dosage, the frequency and duration of treatments, and other considerations. In modern oncology, many regimens combine several chemotherapy drugs in combinat ...
used for all types of AMKL are similar to those used for AML. A final confirmation of safety and efficacy
phase 3 study consisted of 4 cycles of induction therapy with
cytarabine
Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by i ...
and
daunorubicin
Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. I ...
followed by a single course of intensification therapy consisting of cytarabine and
L-asparaginase, and concluded with a
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
consolidation course of 3 additional doses of
intrathecal
Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain ma ...
cytarabine. The dosages of cytarabine in this study were kept low because DS-AMKL patients proved highly susceptible to the toxic effects of the regimen which used a higher cytarabine dosage to treat AML. The low-dose cytarabine regimen achieved excellent results in DS-AMKL with relatively reduced overall toxicity
and is currently recommended as a preferred treatment regimen for the disease.
Autologous hematopoietic stem cell transplantation (i.e. transplantation of
stem cells derived from the individual being transplanted) did not improve relapse-free survival in one large study of DS-AMKL.
Allogenic hematopoietic stem cell transplantation (i.e. transplantation of
stem cells derived another individual) has given better disease-free survival results than autologous transplantation and, based on recent uncontrolled studies, should be considered in DS-AMKL cases that have relapsed after their first chemotherapy-induced complete remission.
Prognosis
The 5-year event free survival, disease-free survival, and overall survival rate in the phase 3 clinical study in DS-AMKL were 79, 89, 84 percent, respectively.
Other studies that use a treatment regimen similar to that used in the phase 3 clinical study report overall survival rates of ~80%
and long-term survivals of 74-91%.
However, DS-AMKL patients who relapse following chemotherapy have a far poorer outlook with 3 year overall survival rate in one study of only 26%. There also appears to be little role for
stem cell transplantation in DS-AMKL given the success of initial chemotherapy and the relatively poor results in DS-AMKL patients given this transplantation.
Non-DS-AMKL
Pathophysiology
The most common genetic abnormality occurring in non-Down-AMKL is a nonreciprocal
translocation between the short or p arm at position 13 on
chromosome 1
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...
(i.e. 1p13) and the p arm at position 13 on
chromosome 22
Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing b ...
(i.e. 22p13).
Nonreciprocal translocations are exchanges of genes between two chromosomes that are not
homologs
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...
, i.e. that are not maternal and paternal copies of the same chromosome. This particular translocation, designated t(1;22)(p13;q13), occurs mainly in infants
but also is seen in children up to the age of 7 years
with non-DS-AMKL. This translocation involves the ''
RBM15'' gene on chromosome 1 and the ''
MKL1
MKL/megakaryoblastic leukemia 1 (also termed MRTFA/myocardin related transcription factor A) is a protein that in humans is encoded by the ''MKL1'' gene.
Function
The protein encoded by this gene is regulated by the actin cytoskeleton and is sh ...
'' gene (also termed MRTFA) on chromosome 22 to create a RBM15-MKL1
fusion gene A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neopla ...
. Studies in mice indicate that the ''Mkl1'' gene (only the first letter of a mouse gene is capitalized) product, MKL1, interacts with the transcription factor
SRF to stimulate the expression of various genes. MKLl is required for the maturation of mouse megakaryoblasts: in its absence, megakaryoblasts and promegakaryocytes proliferate abnormally while megakaryocytes are few in number and have an abnormal
morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
* Morphology (archaeology), study of the shapes or forms of artifacts
* Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies ...
. Mouse studies also indicate that the product of Rbm15, RMB15, interacts with
Nuclear receptor co-repressor 1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 (TRAC-1) is a protein that in humans is encoded by the ''NCOR1'' gene.
NCOR1 is a transcriptional coregulatory protein which c ...
,
Nuclear receptor co-repressor 2
The nuclear receptor co-repressor 2 () is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists ...
(also termed SMRT), and
RBPJ
Recombination signal binding protein for immunoglobulin kappa J region is a protein that in humans is encoded by the ''RBPJ'' gene.
RBPJ also known as CBF1, is the human homolog for the Drosophila
''Drosophila'' () is a genus of flies, belo ...
nuclear proteins to suppress the expression of various genes that are involved in the maturation of platelet,
myeloid and
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
precursor cells. In consequence, the RBM15-MKL1 fusion protein acts in an unregulated fashion to suppress MKL1 targeted genes while stimulating RPBJ target genes. This causes an over-active
Notch signaling pathway and, among other abnormalities, expansion of fetal
hematopoiesis
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells ...
and development of AMKL in a small percentage of adult mice. It is assumed that these events must be accompanied by other, as yet undefined,
oncogenic
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
(i.e., cancer causing) events to explain the development of human non-Down AMKL.
A large number of other genetic abnormalities are associated with the development of non-DS-AMLK.
These include complex chromosomal rearrangements and increases in
copy number
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of d ...
of various genes. Besides the t(1;22)(p13;q13) translocation, common genetic abnormalities in a study of 372 individuals diagnosed with non-DS-AMKL include: rearrangements of genes at position 23 on the long (i.e. q) arm of
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 ...
;
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
* ...
of
chromosome 16
Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cell ...
occurring between p13.3 and q24.3 denoted as inv(16)(p13.3q24.3) that results in the production of a
CBFA2T3-
GLIS2 fusion protein; and increases in chromosome numbers from a normal of 46 to anywhere from 47 to >50. The relationships of these and the many other genetic abnormalities detected in non-Down-AMKL to the disease's development require further investigations.
Presentation
Non-DS-AMKL occurs in neonates, infants, and children of all ages.
Except for the lack of Down syndrome, no history of TMD, and occurrences in children that can be >4 years of age, individuals with non-DS-AMKL present with many of the symptoms, signs, and hematological findings seen in DS-AMKL.
However, non-DS-AMKL is a more aggressive and rapidly progressing disorder than DS-AMKL. Nonetheless, the presentation of non-DS-AMKL is also like DS-AMKL in that it is not often accompanied by one or more extramedullary signs or symptoms of the disease such as liver enlargement, spleen enlargement, leukemia cutis, and leukostasis.
Diagnosis
The diagnosis of non-DS-AMKL is made in children who do not have Down syndrome but exhibit the same clinical symptoms, signs, hematological abnormalities, and specialized laboratory findings seen in DS-AMKL. These children should bear one or more of the genetic aberrations associated with the disease
but not the inactivating GATA1 mutations, extra copies of chromosome 21 genes, or other genetic abnormalities associated with DS-AMKL.
Non-DS-AMKL has many clinical and laboratory features similar to and must be distinguished from
Acute panmyelosis with myelofibrosis, a disorder characterized by bone marrow fibrosis, abnormal megakaryocytes, macrocytic
erythropoiesis
Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.
It is stimulated by decrea ...
, defects in neutrophil production, reduced blood levels of most circulating cells (i.e.
pancytopenia
Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.).
If only two parameters from the complete blood coun ...
), and low levels of circulating blast cells. Analyses of circulating and bone marrow blast cells for features of AMKL (see Diagnosis section of DS-AMKL) and genetic aberrations is helpful in distinguishing the two diseases.
Treatment
In a review of 153 patients treated for non-DS-AMKL between 1990 and 2014 with various intensive chemotherapy protocols that included cytarabine, an
anthracycline
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 canc ...
(e.g.
daunorubicin
Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. I ...
,
doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
), and in 25% of cases human stem cell transplantation, the probability of overall 4 year
survival rate, probability of 4 year event-free survival, and probability of 4 year cumulative relapse rate were 56, 51, and 29%, respectively.
A more recent treatment regimen that is similar to that used to treat DS-AMKL as described above (except it employs the high dose of cytarabine used to treat AML) gives better results and has been recommended for non-DS-AMKL. The response to this regimen approached that seen in non-DS-AMKL, i.e. its complete remission and estimated 10 year survival rates were both 76%.
Similar to DS-AMKL treatment regimens,
allogenic rather than autologous stem cell bone marrow transplantation should be considered in non-DS-AMKL cases that have relapsed following their first chemotherapy-induced complete remission. Further studies may indicate that this recent cancer chemotherapy regimen plus allogenic bone marrow transplantation in cases which relapse after the first remission are the preferred treatment for non-DS-AMKL.
Prognosis
In a review of 153 patients treated for non-DS-AMKL between 1990 and 2014 with various intensive chemotherapy protocols that included cytarabine, an
anthracycline
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 canc ...
(e.g.
daunorubicin
Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. I ...
,
doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
), and in 25% of cases human stem cell transplantation, the probability of overall 4 year
survival rate, probability of 4 year event-free survival, and probability of 4 year cumulative relapse rate were 56, 51, and 29%, respectively. Patients with non-DS-AMKL given the treatment regimen described for DS-AMKL above had a much better prognosis than patients treated with earlier-devised treatment regimens: their overall survival rate using these regimen was estimated to be 76%.
Adult-AMKL
Pathophysiology
Adult-AMKL can result from the progression of other
myeloproliferative neoplasm
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid growt ...
s (MPN) viz.,
chronic myelogenous leukemia,
polycythemia vera
Polycythemia vera is an uncommon myeloproliferative neoplasm (a type of chronic leukemia) in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets.
Most of the healt ...
,
essential thrombocytosis
Essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid le ...
, and
primary myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. ...
.
In one review of adult-AMKL, 25% of 49 cases were considered as secondary to one of these MPN.
The mechanism behind these cases of secondary AMKL are unknown although an
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
* ...
in
chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
at positions q21 and q26, i.e. inv(3)(q21q26), is often seen in these secondary cases of adult-AMKL.
Rare cases of adult-AMKL also have
mediastinal germ cell tumor
Mediastinal germ cell tumors are tumors that derive from germ cell rest remnants in the mediastinum. They most commonly occur in the gonad but occasionally elsewhere.
Signs and symptoms
Unlike benign germ cell tumors of the mediastinum, malignant ...
s. These tumors are malignancies of
germ cell
Germ or germs may refer to:
Science
* Germ (microorganism), an informal word for a pathogen
* Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually
* Germ layer, a primary layer of cells that forms during emb ...
s, i.e. primitive cells that give rise to
sperm and
ovum cells. In adult-AMKL, mediastinal germ cell tumors that are associated with adult-AMKL are not seminomas (i.e. do not originate from the sperm cell line) and occur before or concomitantly with but not after the diagnosis AMKL is made. The three most common genetic aberrations in the bone marrow cells of these individuals (representing ~65% of all cases) were inversions in the p arm of chromosome 12,
trisomy 8
Trisomy 8 causes Warkany syndrome 2, a human chromosomal disorder caused by having three copies (trisomy) of chromosome 8. It can appear with or without mosaicism.
Characteristics
Complete trisomy 8 causes severe effects on the developing fetus ...
, and an extra X chromosome. In several of these cases, the genetic aberrations in the malignant platelet precursor cells were similar to those in the malignant mediastinal germ cells. These results and those of other analyses suggest that the two malignancies derive from a common founding
clone of cells (i.e. a set of genetically identical cells).
Overall, the most common genetic aberrations occurring in adult-AMKL are the previously described inv((3)(q21q26) inversion, translocation between the q arm of chromosome 9 at position 34 and the q arm of chromosome 22 at position 11, i.e. (t(9:22)(q34:q11), and various aberrations in
chromosome 5
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. C ...
or
chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total D ...
. Aberrations in the latter two chromosomes are also commonly seen in an AML that is associated with myelodydplastic-related changes (i.e. predominance of immature blood cells in the bone marrow).
The underlying malignancy-causing mechanism, if any, behind these genetic aberrations requires further study.
Presentation
Adult-AMKL may occur in individuals who have a prior diagnosis of and/or present with chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, primary myelofibrosis, or mediastinal germ cell tumor.
AMKL associated with mediastinal germ cell tumors typically occurs in younger adults, i.e. ages 13–36 (average age 24).
Cases occurring in children aged ≤18 years, which represent ~20% of all cases, could be regarded in the non-DS-AMKL category.
Cases of the disease not associated with mediastinal germ cell tumors occur in adults who as a group have older median age centering around those 50–70 years old. The disorder is far more fulminant than non-DS-AMKL and DS-AMKL and generally presents with more serious hematological symptoms (e.g. anemia-related) and a much higher incidence of extramedullary manifestations (e.g. organ enlargement, leukemia cutis) than seen in the other two forms of AMKL.
Diagnosis
Adult-AMKL commonly occurs in adults in their sixties and seventies but may be seen in adolescents as young as 13. Its diagnosis can be suspected in cases that have either a prior history of MPN or a history or current findings indicating the presence of mediastinal blast cell tumor. In all cases, the diagnosis adult-AMKL rests upon the same determinations used to diagnose DS-AMKL, e.g. increased blast cells in blood and/or bone marrow, immunochemical evidence that these blast cells bear platelet line-specific markers, and occurrence of the genetic aberrations in these blast cells that have been associated with the disease.
Treatment
Adult-AMKL has remained poorly responsive to the treatment regiments used in DS-AMKL and non-DS-AMKL. These treatments have given complete remission rates of 43-50%.
Prognosis
The prognosis of adult-AMKL in patients treated for the disease is far below that of other forms of AMKL. Their median overall survival times are only 18 to 41 weeks with 5 year survival rates of only 10-11 percent. Major improvements in these statistics will likely require new approaches directed at the underlying mechanisms driving the disease.
See also
*
List of hematologic conditions
:''This is an incomplete list, which may never be able to satisfy certain standards for completion.''
There are many conditions of or affecting the human hematologic system—the biological system that includes plasma, platelets, leukocytes, an ...
References
External links
Histologyat
University of Virginia
The University of Virginia (UVA) is a public research university in Charlottesville, Virginia. Founded in 1819 by Thomas Jefferson, the university is ranked among the top academic institutions in the United States, with highly selective ad ...
Imagesat
Nagoya University
* https://rarediseases.info.nih.gov/diseases/524/acute-megakaryoblastic-leukemia (NIH Genetic and Rare Diseases Information Center)
{{Chromosomal abnormalities
Acute myeloid leukemia