Acute promyelocytic leukemia
Encyclopedia
Acute promyelocytic leukemia is a subtype of acute myelogenous leukemia (AML), a cancer
of the blood
and bone marrow
. It is also known as acute progranulocytic leukemia; APL; AML with t(15;17)(q24;q21), PML-RARA and variants; FAB subtype M3 and M3 variant.
In APL, there is an abnormal accumulation of immature granulocytes called promyelocyte
s. The disease is characterized by a chromosomal translocation
involving the retinoic acid receptor
alpha (RARα or RARA) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid
(ATRA) therapy.
Acute promyelocytic leukemia was first characterized in 1957.
From 1950s until the elucidation of its developmental mechanisms in the 1970s, APL had a 100% mortality rate as there was no effective treatment.
s in the marrow starts with the multi-potent hematopietic stem cells (HSC). Several transcription
factors such as PU.1 and C/EB protein alpha have been identified to be important in the white blood cell
differentiation process. The HSC generates the lymphoid
(B cells and T cells of our immune system
) cell line and the myeloid cell lines. The myeloid cell lines have granules in their cytoplasm
and they are called granulocytes and are important in fighting infections.
The accumulation of promyelocytes in the bone marrow results in a reduction in the production of normal red blood cell
s and platelet
s, resulting in anemia
and thrombocytopenia
. The bone marrow is unable to produce healthy red blood cells. Either leukopenia
(low white cell count) or leukocytosis
(high white cell count) may be observed in the peripheral blood.
Symptoms include:
In addition, acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation
(DIC). It is characterized by rapid increase in immature white blood cell
s resulting in rapid progression of the malignant
cell and crowds the bone marrow. This will result in very low red blood cell
s (anemia
) and low platelets which can cause serious bleeding.
APL has a high rate of relapse with conventional chemotherapy
.
for regulation of transcription.
Four other gene rearrangements have been described in APL fusing RARα to promyelocytic leukemia zinc finger (PLZF), nucleophosmin (NPM), nuclear matrix associated (NUMA), or signal transducer and activator of transcription 5b (STAT5B) genes. All of these rearrangements are ATRA-sensitive, except for PLZF/RARα, which is resistant to ATRA.
The fusion of PML and RAR creates a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR)molecule and histone deacetylase (HDACL). Although the chromosomal translocation involving RARα is believed to be the initiating event, additional mutations are required for the development of leukemia.
APL most distinguishable trait is the presence of overt coagulopathy (disseminated intravascular coagulation) at diagnosis. The bleeding diathesis is due to the enhanced fibrinolytic activity due to annexin II overexpression and expression of tissue factor by abnormal promyelocytes.
The hypergranular form of APL features faggot cells. This term is applied to these blast cells because of the presence of numerous Auer rods
in the cytoplasm
. The accumulation of these Auer rods gives the appearance of a bundle of sticks, from which the cells derive their name.
(PCR), fluorescent in situ hybridization
(FISH), or conventional cytogenetics
of peripheral blood or bone marrow. This mutation involves a translocation of the long arm chromosomes of 15 and 17.
RARα is a member of the nuclear family of receptors; its ligand, retinoic acid
is a form of Vitamin A
and acts as a regulator of DNA transcription at multiple sites.
Monitoring for relapse using PCR tests for PML/RARα transcript allows early re-treatment which is successful in many instances.
. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant
action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA is typically combined with anthracycline
based chemotherapy resulting in a clinical remission in approximately 90% of patients. ATRA alone is capable of inducing remission but it is short-lived in the absence of anthracycline. Arsenic trioxide
is currently being evaluated for treatment of relapsed / refractory disease. After stable remission is induced, the standard of care is to undergo 2 years of consolidation chemotherapy with Methotrexate
, Mercaptopurine, and ATRA. Nearly all patients will relapse without consolidation therapy.
ATRA therapy is associated with the unique side effect of retinoic acid syndrome
. This is associated with the development of dyspnea
, fever, weight gain, peripheral edema
and is treated with dexamethasone
. The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.
Allogeneic bone marrow or stem cell transplantation are the preferred treatment options for relapsed or refractory disease. Remission with arsenic trioxide has been reported.
Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. Arsenic also increases caspase activity which then induces apoptosis
. It does reduce the relapse rate for high risk patients.
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
of the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. It is also known as acute progranulocytic leukemia; APL; AML with t(15;17)(q24;q21), PML-RARA and variants; FAB subtype M3 and M3 variant.
In APL, there is an abnormal accumulation of immature granulocytes called promyelocyte
Promyelocyte
A promyelocyte is a granulocyte precursor, developing from the myeloblast and developing into the myelocyte.-External links: - "18. Bone Marrow and Hemopoiesis: bone marrow smear, promyelocyte and erythroblasts " "Bone marrow" "Bone marrow"* - "Bone marrow smear"...
s. The disease is characterized by a chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
involving the retinoic acid receptor
Retinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
alpha (RARα or RARA) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid
Atra
Atra or ATRA can refer to:*Atra, Estonia, village in Palupera Parish, Valga County, Estonia*Stachybotrys chartarum*All-trans retinoic acid*American Tort Reform Association*the location of an Arabic fortress west of the Tigris...
(ATRA) therapy.
Acute promyelocytic leukemia was first characterized in 1957.
From 1950s until the elucidation of its developmental mechanisms in the 1970s, APL had a 100% mortality rate as there was no effective treatment.
Signs and symptoms
Normal differentiation of the white blood cellWhite blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s in the marrow starts with the multi-potent hematopietic stem cells (HSC). Several transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
factors such as PU.1 and C/EB protein alpha have been identified to be important in the white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
differentiation process. The HSC generates the lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
(B cells and T cells of our immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
) cell line and the myeloid cell lines. The myeloid cell lines have granules in their cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
and they are called granulocytes and are important in fighting infections.
The accumulation of promyelocytes in the bone marrow results in a reduction in the production of normal red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s and platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s, resulting in anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
. The bone marrow is unable to produce healthy red blood cells. Either leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
(low white cell count) or leukocytosis
Leukocytosis
Leukocytosis is a raised white blood cell count above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, and is observed in certain parasitic infections...
(high white cell count) may be observed in the peripheral blood.
Symptoms include:
- Fatigue, weakness, shortness of breath (from anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
)-the decrease of normal red blood cellRed blood cellRed blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
production or lack thereof. - Easy bruising and bleeding (from thrombocytopenia and coagulopathyCoagulopathyCoagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...
, which prevents blood clotting) - Fever and infection (from lack of normal white blood cells)
- Enlargement of the spleen may cause minor abdominal discomfort
In addition, acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation
Disseminated intravascular coagulation
Disseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...
(DIC). It is characterized by rapid increase in immature white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s resulting in rapid progression of the malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
cell and crowds the bone marrow. This will result in very low red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s (anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
) and low platelets which can cause serious bleeding.
Epidemiology
Acute promyelocytic leukemia represents 5-8% of AML in adults. The median age is approximately 40 years, which is considerably younger than the other subtypes of AML (70 years). Without proper medicine and treatment, APL is fatal. The incidence is increased in patients originated in Latin American countries.APL has a high rate of relapse with conventional chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
Pathogenesis
Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17 (RARα). In 95% of cases of APL, retinoic acid receptor-alpha (RARα) gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene (PML) on chromosome 15, a translocation denoted as t(15;17)(q24;q21). The RAR receptor is dependent on retinoic acidRetinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
for regulation of transcription.
Four other gene rearrangements have been described in APL fusing RARα to promyelocytic leukemia zinc finger (PLZF), nucleophosmin (NPM), nuclear matrix associated (NUMA), or signal transducer and activator of transcription 5b (STAT5B) genes. All of these rearrangements are ATRA-sensitive, except for PLZF/RARα, which is resistant to ATRA.
The fusion of PML and RAR creates a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR)molecule and histone deacetylase (HDACL). Although the chromosomal translocation involving RARα is believed to be the initiating event, additional mutations are required for the development of leukemia.
APL most distinguishable trait is the presence of overt coagulopathy (disseminated intravascular coagulation) at diagnosis. The bleeding diathesis is due to the enhanced fibrinolytic activity due to annexin II overexpression and expression of tissue factor by abnormal promyelocytes.
The hypergranular form of APL features faggot cells. This term is applied to these blast cells because of the presence of numerous Auer rods
Auer rods
Auer rods can be seen in the leukemic blasts of acute myeloid leukemia. Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts...
in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. The accumulation of these Auer rods gives the appearance of a bundle of sticks, from which the cells derive their name.
Diagnosis
Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. Definitive diagnosis requires testing for the PML/RARα fusion gene. This may be done by polymerase chain reactionPolymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
(PCR), fluorescent in situ hybridization
Fluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
(FISH), or conventional cytogenetics
Cytogenetics
Cytogenetics is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-Banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ...
of peripheral blood or bone marrow. This mutation involves a translocation of the long arm chromosomes of 15 and 17.
RARα is a member of the nuclear family of receptors; its ligand, retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
is a form of Vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
and acts as a regulator of DNA transcription at multiple sites.
Monitoring for relapse using PCR tests for PML/RARα transcript allows early re-treatment which is successful in many instances.
Treatment
APL is unique among myeloid leukemias due to its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin AVitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant
Aberrant
Aberrant is a role-playing game created by White Wolf Game Studio in 1999, set in 2008 in a world where super-powered humans started appearing one day in 1998. It is the middle setting in the greater Trinity Universe timeline, chronologically situated about 90 years after Adventure!, White Wolf's...
action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA is typically combined with anthracycline
Anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
based chemotherapy resulting in a clinical remission in approximately 90% of patients. ATRA alone is capable of inducing remission but it is short-lived in the absence of anthracycline. Arsenic trioxide
Arsenic trioxide
Arsenic trioxide is the inorganic compound with the formula As2O3. This commercially important oxide of arsenic is the main precursor to other arsenic compounds, including organoarsenic compounds. Approximately 50,000 tonnes are produced annually...
is currently being evaluated for treatment of relapsed / refractory disease. After stable remission is induced, the standard of care is to undergo 2 years of consolidation chemotherapy with Methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, Mercaptopurine, and ATRA. Nearly all patients will relapse without consolidation therapy.
ATRA therapy is associated with the unique side effect of retinoic acid syndrome
Retinoic acid syndrome
Retinoic acid syndrome is a potentially life threatening complication observed in patients with acute promyelocytic leukemia and first thought to be specifically associated with all-trans retinoic acid treatment...
. This is associated with the development of dyspnea
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
, fever, weight gain, peripheral edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
and is treated with dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.
Allogeneic bone marrow or stem cell transplantation are the preferred treatment options for relapsed or refractory disease. Remission with arsenic trioxide has been reported.
Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. Arsenic also increases caspase activity which then induces apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. It does reduce the relapse rate for high risk patients.
External links
- Histology at University of VirginiaUniversity of VirginiaThe University of Virginia is a public research university located in Charlottesville, Virginia, United States, founded by Thomas Jefferson...
- Images at Nagoya UniversityNagoya UniversityNagoya University is one of the most prestigious universities in Japan. It can be seen in the several rankings such as shown below.-General Rankings:...