Acute Promyelocytic Leukemia (APL) with PML-RARA
Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D.
Acute Myeloid Leukaemia
Cancer Sub-Classification / Subtype
Acute Promyelocytic Leukemia (APL) with PML-RARA
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system, and associated French-American-British (FAB) classification is acute promyelocytic leukemia (APL, M3).
Synonyms / Terminology
APL with t(15;17)(q24.1;q21.1)
AML with t(15;17)(q24.1;q21.1)
Epidemiology / Prevalence
Accounts for 5-8% of AML, may occur at any age, but predominantly in adult in mid-life.
Typical (hypergranular) and microgranular (hypogranular) APL are frequently associated with disseminated intravascular coagulation (DIC). In contrast to typical APL, microgranular APL is associated with increased counts of leukocytes which have rapid doubling time.
Sites of Involvement
The abnormal promyelocytes of typical APL have irregular and variable nuclear size and shapes. They are frequently kidney-shaped or bilobed. The cytoplasm is characterized by large granules and stains bright pink, red or purple in Romanowsky staining. In most cases, there are bundles of Auer rods (“faggot cells”) in the cytoplasm. Myeloblasts with single Auer rods may also be present. Auer rods in typical APL are usually larger than those in other types of AML. Microgranular APL is characterized by apparent paucity or absence of granules and predominantly bilobed nuclear shape. The myeloperoxidase (MPO) reaction for both typical and microgranular APL is positive.
|Positive (universal)||CD13, CD33, CD117, myeloperoxidase (MPO)|
|Positive (subset)||CD2 (microgranular APL), CD34 (microgranular APL), CD56 (20% of APL, associated with a worse outcome)|
|Negative (universal)||HLA-DR, CD15, CD11a, CD11b, CD11c, CD18|
|Negative (subset)||CD2 (typical APL), CD34 (typical APL)|
Chromosomal Rearrangements (Gene Fusions)
This AML subtype is classified based on the presence of a PML-RARA fusion, which results from fusion of the 5’ portion of PML at 15q24.1 and the 3’ portion of RARA at 17q21.1. 5'PML-3'RARA transcript is expressed in all cases, and 5'RARA-3'PML transcript is found in 2/3 of cases. Rare cases of APL have cryptic t(15;17)(q24.1;q21.1) such as submicroscopic insertion of RARA into PML leading to the expression of the PML-RARA transcript or three way translocations involving chromosomes 15 and 17 with an additional chromosome. Several variant translocations involving RARA have also been identified, including t(11;17) and t(5;17). The 4th edition revision to the World Health Organization renamed APL with t(15;17)(q24.1;q21.1) as APL with PML-RARA.
|Chromosomal Rearrangement||Genes in Fusion (5’ or 3’ Segments)||Pathogenic Derivative||Prevalence|
|t(15;17)(q24.1;q21.1)||5'PML / 3'RARA||der(15)||5-8% of AML|
Characteristic Chromosomal Aberrations / Patterns
Gene Mutations (SNV/INDEL)
There is not specific information on mutations related to this subtype of AML at this time.
|Concomitant Mutations||34-45% of APL have FLT3 mutations.|
|Secondary Mutations||About 40% of APL cases have secondary cytogenetic abnormalities with trisomy 8 being the most frequent (10-15%).|
|Mutually Exclusive||Not applicable|
Genes and Main Pathways Involved
The protein encoded by the PML (promyelocytic leukemia) gene is a member of the tripartite motif (TRIM) family and it functions as a transcription factor and tumor suppressor. PML is the core component of subnuclear structures called PML nuclear bodies (PML-NBs) and it interacts with a large number of proteins including p53 and has been implicated in several cellular functions such as cellular senescence, apoptosis, and hematopoietic stem cell maintenance. The gene RARA (Retinoic acid receptor, alpha) encodes a nuclear retinoic acid receptor which regulates transcription in a ligand-dependent manner. The fusion of PML and RARA results in expression of a hybrid protein with altered functions. This fusion protein deregulates transcriptional control such as RAR targets and disrupts PML nuclear bodies.
Diagnostic Testing Methods
Karyotype, FISH, RT-PCR
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
APL can be differentiated from other types of AML based on microscopic examination of the blood, bone marrow, or biopsy as well as detection of the PML/RARA fusion gene. The prognosis in APL treated with all-trans retinoic acid (ATRA) and arsenic trioxide is favorable, and relapsed or refractory APL cases show a generally good response with arsenic trioxide therapy. Expression of CD56 is associated with poor prognosis, while the prognostic significance of FLT3 -ITD mutations remains unclear.
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*Citation of this Page: Zhong Y, Piazza M, and Shetty S. “Acute Promyelocytic Leukemia (APL) with PML-RARA”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/2/2021, https://ccga.io/index.php/Acute Promyelocytic Leukemia (APL) with PML-RARA.