Acute promyelocytic leukemia

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Acute promyelocytic leukemia
Classification and external resources
Neutrophilic promyelocyte
ICD-10	C92.4
ICD-9	205.0
ICD-O:	M9866/3
OMIM	102578
eMedicine	med/34
MeSH	D015473

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)(q22;q12), PML-RARA and variants; FAB subtype M3^[1] and M3 variant.

In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. 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.^[2] During the 1950s through 1970s APL was 100 percent fatal and there was no effective treatment. No one knew how the cancer formed.

Signs and symptoms

Normal differentiation of the white blood cells in the marrrow starts with the multi-potent hematopietic stem cells (HSC). Regulation of gene expression can include both inhibitory and inductive mechanism.^[3] Several transcription factors such as PU.1 and C/EB protein alapha have been identified to be important in the white blood cell differentiation process.^[4] 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.^[5]

The accumulation of promyelocytes in the bone marrow results in a reduction in the production of normal red blood cells and platelets, 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:

• Fatigue, weakness, shortness of breath (from anemia)-the decrease of normal red blood cell production or lack there of.
• Easy bruising and bleeding (from thrombocytopenia and coagulopathy) which causes 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 (DIC). It is characterized by rapid increase in immature white blood cells resulting in rapid progression of the malignant cell and crowds the bone marrow. This will result in very low red blood cells (anemia) 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.^[6]

APL has a high rate of relapse with conventional chemotherapy.^[7]

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)(q22;q12). The RAR receptor is dependent on retinoic acid for regulation of transcription. ^[8]

Four other gene rearrangements have been described in APL fusing RARα to promyelocytic leukemia zinc finger (PLZF)^[9], nucleophosmin (NPM), nuclear matrix associated (NUMA), or signal transducer and activator of transcription 5b (STAT5B) genes.

The fusion of PML and RAR creates a hybrid protein with altered functions. This fusion protein disrupts the function of RARα and blocks the normal maturation of granulocytes. The hybrid protein represses transcription and blocks cell differentiation by enhancing interaction of nuclear co-repressor (NCOR)molecule and histone deacetylase (HDACL).^[10] Although the chromosomal translocation involving RARα is believed to be the initiating event, additional mutations are required for the development of leukemia.

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.

Diagnosis

Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow biopsy or aspirate as well as finding the characteristic mutation. Definitive diagnosis requires testing for the RARα fusion gene. This may be done by polymerase chain reaction (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.

The RAR is a member of the steroid hormone receptor family acid and is a form of Vitamin A and it is depended on retinoic acid for the regulation of transcription.^[11]

Monitoring for relapse using PCR tests for RARα allows early re-treatment which is successful in many instances.

Treatment

APL is unique among the leukemias distinguished by its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action, reprograming the leukemic cell into a normally functioning cell rather than killing it as conventional chemotherapy does. ATRA is typically combined with anthracycline based chemotherapy resulting in a clinical remission in approximately 90% of patients. Complete remission can occur when patients are treated with high doses of vitamin A in the form of all- "trans"retenoic acid or (ATRA) and with arsenic.

ATRA therapy is associated with the unique side effect of retinoic acid syndrome.^[12] 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.

Bone marrow transplant and Allogeneic stem cell transplant is the prefered treatment options for APL. Remission with use of arsenic trioxide has been reported.^[13] Arsenic is a natural subtance which has been used for 2,000 years in Chinese medicine^[14]. Studies have shown arensic reorganized the nuclear bodies and degrades the mutant PML-RAR fusion protein.^[15] Arsenic also increases caspases which then induces apoptosis.^[16] It does reduce the relapse rate for high risk patients.^[17]

References

External links

• Histology at University of Virginia
• Images at Nagoya University