Acute promyelocytic leukaemia with PML::RARA fusion
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis 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.
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
Primary Author(s)*
Yiming Zhong, Ph.D., Megan Piazza, Ph.D., and Shashi Shetty, Ph.D.
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Acute myeloid leukaemia |
| Type | Acute myeloid leukaemia with defining genetic abnormalities |
| Subtype(s) | Acute promyelocytic leukaemia with PML::RARA fusion |
WHO Essential and Desirable Genetic Diagnostic Criteria
(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)
| WHO Essential Criteria (Genetics)* | |
| WHO Desirable Criteria (Genetics)* | |
| Other Classification |
*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
Related Terminology
(Instructions: The table will have the related terminology from the WHO autocompleted.)
| Acceptable | |
| Not Recommended |
Gene Rearrangements
Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE: ABL1 | EXAMPLE: BCR::ABL1 | EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | EXAMPLE: t(9;22)(q34;q11.2) | EXAMPLE: Common (CML) | EXAMPLE: D, P, T | EXAMPLE: Yes (WHO, NCCN) | 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). BCR::ABL1 is generally favorable in CML (add reference). |
| EXAMPLE: CIC | EXAMPLE: CIC::DUX4 | EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. | EXAMPLE: t(4;19)(q25;q13) | EXAMPLE: Common (CIC-rearranged sarcoma) | EXAMPLE: D | EXAMPLE:
DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references). | |
| EXAMPLE: ALK | EXAMPLE: ELM4::ALK
|
EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. | EXAMPLE: N/A | EXAMPLE: Rare (Lung adenocarcinoma) | EXAMPLE: T | EXAMPLE:
Both balanced and unbalanced forms are observed by FISH (add references). | |
| EXAMPLE: ABL1 | EXAMPLE: N/A | EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. | EXAMPLE: N/A | EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) | EXAMPLE: D, P, T | ||
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.
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[1]. 5'PML-3'RARA transcript is expressed in all cases, and 5'RARA-3'PML transcript is found in 2/3 of cases[2]. 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[3]. Several variant translocations involving RARA have also been identified, including t(11;17) and t(5;17)[3]. The 4th edition revision to the World Health Organization renamed APL with t(15;17)(q24.1;q21.1) as APL with PML-RARA[4][5].
| 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 |
End of V4 Section
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please 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[6][7]. Expression of CD56 is associated with poor prognosis, while the prognostic significance of FLT3 -ITD mutations remains unclear[8][9].
End of V4 Section
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE: 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 references). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references). | |
| EXAMPLE:
17 |
EXAMPLE: Amp | EXAMPLE:
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb] |
EXAMPLE:
ERBB2 |
EXAMPLE: D, P, T | EXAMPLE:
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined. | |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.
Not applicable
End of V4 Section
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here and fill in the table (Instructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| EXAMPLE:
Co-deletion of 1p and 18q |
EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). | EXAMPLE: Common (Oligodendroglioma) | EXAMPLE: D, P | ||
| EXAMPLE:
Microsatellite instability - hypermutated |
EXAMPLE: Common (Endometrial carcinoma) | EXAMPLE: P, T | |||
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.
Not applicable
End of V4 Section
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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.
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[4]. |
| Secondary Mutations | About 40% of APL cases have secondary cytogenetic abnormalities with trisomy 8 being the most frequent (10-15%)[4]. |
| Mutually Exclusive | Not applicable |
End of V4 Section
Epigenomic Alterations
Not applicable
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the 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 |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.
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[10][11]. The gene RARA (Retinoic acid receptor, alpha) encodes a nuclear retinoic acid receptor which regulates transcription in a ligand-dependent manner[12]. 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[13].
End of V4 Section
Genetic Diagnostic Testing Methods
Karyotype, FISH, RT-PCR
Familial Forms
Not applicable
Additional Information
Not applicable
Links
References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)
- ↑ 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.
- ↑ Jump up to: 3.0 3.1 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.
- ↑ Jump up to: 4.0 4.1 4.2 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.
- ↑ 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 Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
*Citation of this Page: “Acute promyelocytic leukaemia with PML::RARA fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/11/2025, https://ccga.io/index.php/HAEM5:Acute_promyelocytic_leukaemia_with_PML::RARA_fusion.