HAEM5:Acute promyelocytic leukaemia with PML::RARA fusion

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This 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).

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.

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the 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)

editv4:Clinical Features

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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

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.

Immunophenotype

The immunophenotype has been well characterized.

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)

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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).

editv4:Chromosomal Rearrangements (Gene Fusions)

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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

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. Expression of CD56 is associated with poor prognosis, while the prognostic significance of FLT3 -ITD mutations remains unclear.

Individual Region Genomic Gain / Loss / LOH

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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).

editv4:Genomic Gain/Loss/LOH

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Not 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)

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).

editv4:Characteristic Chromosomal Aberrations / Patterns

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Not applicable

Gene Mutations (SNV / INDEL)

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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.

editv4:Gene Mutations (SNV/INDEL)

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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.
Secondary Mutations	About 40% of APL cases have secondary cytogenetic abnormalities with trisomy 8 being the most frequent (10-15%).
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.)

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 Involved

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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.

Genetic Diagnostic Testing Methods

Karyotype, FISH, RT-PCR

Familial Forms

Not applicable

Additional Information

Not applicable

Links

PML

RARA

References

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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 09/6/2024, https://ccga.io/index.php/HAEM5:Acute_promyelocytic_leukaemia_with_PML::RARA_fusion.