Acute promyelocytic leukaemia with PML::RARA fusion
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editHAEM5 Conversion NotesThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4: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
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)
| Signs and Symptoms | EXAMPLE: Asymptomatic (incidental finding on complete blood counts)
EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE: Cytopenias
EXAMPLE: Lymphocytosis (low level) |
editHAEM5 Conversion NotesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationTypical (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)
Put your text here and fill in the table
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: 3'ABL1 / 5'BCR | EXAMPLE: der(22) | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add reference) |
Yes | No | Yes | EXAMPLE:
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editHAEM5 Conversion NotesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis 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
editHAEM5 Conversion NotesPlease incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
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[8][9]. Expression of CD56 is associated with poor prognosis, while the prognostic significance of FLT3 -ITD mutations remains unclear[10][11].
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.)
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7:1- 159,335,973 [hg38] |
EXAMPLE:
chr7 |
Yes | Yes | No | EXAMPLE:
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8:1-145,138,636 [hg38] |
EXAMPLE:
chr8 |
No | No | No | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add reference). |
editHAEM5 Conversion NotesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationNot applicable
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editHAEM5 Conversion NotesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationNot applicable
Gene Mutations (SNV / INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.)
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editHAEM5 Conversion NotesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThere 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
Epigenomic Alterations
Not applicable
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editHAEM5 Conversion NotesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThe 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[12][13]. The gene RARA (Retinoic acid receptor, alpha) encodes a nuclear retinoic acid receptor which regulates transcription in a ligand-dependent manner[14]. 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[15].
Genetic Diagnostic Testing Methods
Karyotype, FISH, RT-PCR
Familial Forms
Not applicable
Additional Information
Not applicable
Links
References
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- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 6.0 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.
- ↑ 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.
- ↑ "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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “Acute promyelocytic leukaemia with PML::RARA fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/1/2024, https://ccga.io/index.php/HAEM5:Acute_promyelocytic_leukaemia_with_PML::RARA_fusion.