Acute promyelocytic leukemia (APML, APL) is a subtype of acute myeloid leukemia (AML), a cancer of the white blood cells. 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 distinguished from other forms of AML by its responsiveness to all-trans retinoic acid (ATRA; also known as tretinoin) therapy. Acute promyelocytic leukemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week. Today, prognoses have drastically improved; 10-year survival rates are estimated to be approximately 80-90% according to one study.

Signs and symptoms

The symptoms tend to be similar to AML in general with the following being possible symptoms:

• Anemia
• Fatigue
• Weakness
• Chills
• Depression
• Difficulty breathing (dyspnea)
• Low platelets (thrombocytopenia) leading to easy bleeding
• Fever
• Infection as a result of low neutrophils (neutropenia)
• Elevated white blood cells (leukocytosis)
• Coagulopathy (including DIC)
• Bicytopenia

Easy bleeding from low platelets may include:

• Bruising (ecchymosis)
• Gingival bleeding
• Nose bleeds (epistaxis)
• Increased menstrual bleeding (menorrhagia)

Pathogenesis

Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17 (RARA).  In 95% of cases of APL, retinoic acid receptor-alpha (RARA) 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 acid for regulation of transcription.

Eight other rare gene rearrangements have been described in APL fusing RARA to promyelocytic leukemia zinc finger (PLZF also known as ZBTB16),  nucleophosmin (NPM1), nuclear matrix associated (NUMA1), signal transducer and activator of transcription 5b (STAT5B), protein kinase A regulatory subunit 1α (PRKAR1A), factor interacting with PAPOLA and CPSF1 (FIP1L1), BCL6 corepressor (BCOR) or oligonucleotide/oligosaccharide-binding fold containing 2A (OBFC2A also known as NABP1) genes. Some of these rearrangements are ATRA-sensitive or have unknown sensitivity to ATRA because they are so rare; STAT5B/RARA and PLZF/RARA are known to be resistant to ATRA.

Diagnosis

Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the blood film or a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. The presence of promyelocytes containing multiple Auer rods (termed faggot cells) on the peripheral blood smear is highly suggestive of acute promyelocytic leukemia. Definitive diagnosis requires testing for the PML/RARA 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 of chromosomes 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected by cytogenetic testing; on these occasions PCR testing is essential to confirm the diagnosis.

Treatment

• Initial treatment
• Maintenance therapy
• Relapsed or refractory disease
• Investigational agents

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