Acute Promyelocytic Leukemia (APL) with PML-RARA

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Primary Author(s)*

Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D.

Cancer Category/Type

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)[1].

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[1].

Clinical Features

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[1].

Sites of Involvement

Bone marrow

Morphologic Features

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[1].

Immunophenotype

The immunophenotype has been well characterized[1][2][3].

Finding Marker
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[4]. 5'PML-3'RARA transcript is expressed in all cases, and 5'RARA-3'PML transcript is found in 2/3 of cases[5]. 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[6]. Several variant translocations involving RARA have also been identified, including t(11;17) and t(5;17)[6]. The 4th edition revision to the World Health Organization renamed APL with t(15;17)(q24.1;q21.1) as APL with PML-RARA[1][7].

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

Not applicable

Genomic Gain/Loss/LOH

Not applicable

Gene Mutations (SNV/INDEL)

There is not specific information on mutations related to this subtype of AML at this time.

Other Mutations

Type Gene/Region/Other
Concomitant Mutations 34-45% of APL have FLT3 mutations[1].
Secondary Mutations About 40% of APL cases have secondary cytogenetic abnormalities with trisomy 8 being the most frequent (10-15%)[1].
Mutually Exclusive Not applicable

Epigenomics (Methylation)

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[8][9]. The gene RARA (Retinoic acid receptor, alpha) encodes a nuclear retinoic acid receptor which regulates transcription in a ligand-dependent manner[10]. 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[11].

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[12][13]. Expression of CD56 is associated with poor prognosis, while the prognostic significance of FLT3 -ITD mutations remains unclear[14][15].

Familial Forms

Not applicable

Other Information

Not applicable

Links

PML

RARA

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p134-136.
  2. Dong, Henry Y.; et al. (2011). "Flow cytometry rapidly identifies all acute promyelocytic leukemias with high specificity independent of underlying cytogenetic abnormalities". American Journal of Clinical Pathology. 135 (1): 76–84. doi:10.1309/AJCPW9TSLQNCZAVT. ISSN 1943-7722. PMID 21173127.
  3. Gorczyca, Wojciech (2012). "Acute promyelocytic leukemia: four distinct patterns by flow cytometry immunophenotyping". Polish Journal of Pathology: Official Journal of the Polish Society of Pathologists. 63 (1): 8–17. ISSN 1233-9687. PMID 22535601.
  4. de Thé, H.; et al. (1990). "The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus". Nature. 347 (6293): 558–561. doi:10.1038/347558a0. ISSN 0028-0836. PMID 2170850.
  5. Warrell, R. P.; et al. (1993). "Acute promyelocytic leukemia". The New England Journal of Medicine. 329 (3): 177–189. doi:10.1056/NEJM199307153290307. ISSN 0028-4793. PMID 8515790.
  6. 6.0 6.1 Grimwade, D.; et al. (1997). "Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia". Blood. 90 (12): 4876–4885. ISSN 0006-4971. PMID 9389704.
  7. Arber, Daniel A.; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
  8. Pearson, M.; et al. (2000). "PML regulates p53 acetylation and premature senescence induced by oncogenic Ras". Nature. 406 (6792): 207–210. doi:10.1038/35018127. ISSN 0028-0836. PMID 10910364.
  9. Bernardi, Rosa; et al. (2007). "Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies". Nature Reviews. Molecular Cell Biology. 8 (12): 1006–1016. doi:10.1038/nrm2277. ISSN 1471-0080. PMID 17928811.
  10. Melnick, A.; et al. (1999). "Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia". Blood. 93 (10): 3167–3215. ISSN 0006-4971. PMID 10233871.
  11. de Thé, Hugues; et al. (2010). "Acute promyelocytic leukaemia: novel insights into the mechanisms of cure". Nature Reviews. Cancer. 10 (11): 775–783. doi:10.1038/nrc2943. ISSN 1474-1768. PMID 20966922.
  12. "Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72(2):567-572". Blood. 128 (26): 3017. 2016. doi:10.1182/blood-2016-11-750182. ISSN 1528-0020. PMID 28034863.
  13. de Thé, Hugues; et al. (2017). "Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure". Cancer Cell. 32 (5): 552–560. doi:10.1016/j.ccell.2017.10.002. ISSN 1878-3686. PMID 29136503.
  14. Ferrara, F.; et al. (2000). "CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated with simultaneous all-trans-retinoic acid and chemotherapy". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 18 (6): 1295–1300. doi:10.1200/JCO.2000.18.6.1295. ISSN 0732-183X. PMID 10715300.
  15. Schnittger, Susanne; et al. (2011). "Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA". Haematologica. 96 (12): 1799–1807. doi:10.3324/haematol.2011.049007. ISSN 1592-8721. PMC 3232262. PMID 21859732.

Notes

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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.