t(15;17)(q24;q21) PML/RARA

2016-03-01   Pino J. Poddighe  , Pino J. Poddighe  

1.Department of Clinical Genetics, VU University Medical Center, Amsterdam (PJP); Department of Human Genetics, Radboud University Nijmegen Medical Centre (DOW), The Netherlands. p.poddighe@vumc.nl; Daniel.OldeWeghuis@radboudumc.nl
2.Laboratoire de Biologie Cellulaire Hématopoïétique, EP-107 CNRS, Institut d Hématologie, Hôpital Saint Louis, Centre Hayem, Paris, France
3.Laboratoire de Biologie Cellulaire Hématopoïétique, EP-107 CNRS, Institut dHématologie, Hôpital Saint Louis, Centre Hayem, Paris, France

Abstract

Review on t(15;17)(q24;q21), with data on clinics, and the genes involved.

Clinics and Pathology

Disease

Acute promyelocytic leukaemia (APL), subtype of acute myeloid leukaemia (AML). Mostly de novo; a very few cases of t(15;17) in therapy-related leukaemia (t-APL) have been reported.
In sporadic cases the t(15;17) can be present in chronic myelogenous leukemia (CML) in myeloid blast crisis as an additional abnormality to the t(9;22)(q34;q11.2).

Phenotype stem cell origin

t(15;17) is quasi pathognomonic of APL. Both hypergranular or "typical" APL and microgranular (hypogranular) types exist.

Epidemiology

Found in 10% of adult AML; annual incidence: 1 per 106, similar to the incidence of the t(8;21)(q22;q22). The disease can occur at any age, but patients are predominantly adult in mid-life; sex ratio 1M/1F (WHO 2008).

Clinics

Typical and microgranular APL are frequently associated with disseminated intravascular coagulation (DIC). In microgranular APL, unlike typical APL, the leukocyte count is very high, with rapid doubling time. WBC and platelets may be lower than in other AMLs.
Atlas Image
t(15;17)(q24;21) is associated conbsistently with AML M3. This chromosomal abnormality first appeared to be confined to the characteristic or morphologically typical M3 AML or "hypergranular promyelocytic leukemia", defined by bone marrow replacement with highly granulated blast cells. The nuclear size and shape is irregular and highly variable; they are often kidney-shaped or bilobed. The cytoplasm is completely occupied by densely packed or even coalescent large granules, staining bright pink, red or purple by MGG. In some cells the cytoplasm is filled with fine dust-like granules. Characteristic cells containing bundles of Auer rods ("faggot cells") randomly distributed in the cytoplasm, although frequent, are not present in all cases. Auer rods in M3 are usually larger than in other AML and they may have a characteristic morphology at the ultrastructural level. In some cases, the cytoplasmic granules are so large and/or numerous that they totally obscure the cell, rendering the nuclear cytoplasmic limit indistinct. In M3 AML, MPO is always strongly positive in all blast cells, with the reaction product covering the whole cytoplasm and often the nucleus too - Text and iconography Courtesy Georges Flandrin 2001.

Cytology

Large cells with myeloperoxidase positive cytoplasmic granulations (microgranular forms are called variant or hypogranular APL, and are often hyperleucocytic); bundles of Auer rods. The typical morphology shows abnormal, usually bilobed hypergranular promyelocytes. Sudan Black (SB) is always strongly positive in all blast cells (WHO 2008).

Treatment

One of the rare leukaemias where treatment is an emergency, as intra vascular coagulation is prominent, causing a high rate (10 to 40%) of early mortality, mainly due to cerebral haemorrhage.
With the recent differentiation therapy using all-trans retinoic acid ATRA (with combined cytotoxic chemotherapy or arsenic trioxide (ATO)), complete remission (CR) is obtained in more than 90% of cases; this is the only cancer which, to date, can be treated by differentiation therapy.

Prognosis

The prognosis in APL, treated optimally with ATRA and an anthracycline, is more favourable than for any other AML cytogenetic subtype, and cases of relapsed or refractory APL show a generally good response with arsenic trioxide therapy. Expression of DC56 is associated with a less favourable prognosis, (Ferrara et al 2000) while the prognostic significance of FLT3 -ITD mutations in this disease remains unclear (Kuchenbauer et al 2005). Survival at 1 yr and at 3 yrs are stable at 70%, instead of a 30 to 40% 3 yr survival previously.

Cytogenetics

Cytogenetics morphological

Classic translocation t(15;17)(q24;q21). The translocation may be overlooked in traditional karyotyping. Interphase FISH is indicated, preferably urgent (within 8 hours) on bone marrow aspirate cells (see Figure 1).
Although primary anomaly in most cases, t(15;17) can also occur in rare occurrences at acutisation (of promyelocytic type, of course) of a CML with the usual t(9;22).
Atlas Image
FISH with the LSI PML/RARA Dual Color Dual Fusion Translocation Probe (Abbott) on a bone marrow cell sample, showing a metaphase spread and one interphase nucleus with two PML-RARA fusion signals (arrows), and one normal interphase cell with two red and two green signals. Courtesy Hossein Mossafa.

Additional anomalies

Secondary cytogenetic abnormalities are noted in about 40% of cases, +8 most frequent (10-15%); del (7q) ; del(9q) rare.

Genes Involved and Proteins

Note
The sensitivity of APL cells (both hypergranular and hypogranular forms) to ATRA has led to the discovery that the retinoic acid receptor alpha (RARA) gene on chromosome band 17q21 fuses with a nuclear regulatory factor gene on chromosome band 15q24 (PML gene) giving rise to a PML-RARA fusion gene product.
Rare cases of APL lacking the classic translocation in routine cytogenetic studies have been described with complex variant translocations (true variants) involving both chromosomes 15 and 17 with an additional chromosome (three way translocations) or with submicroscopic insertion of RARA into PML leading to the expression of the PML-RARA transcript; these latter cases are considered as cryptic or masked t(15;17)(q24;q21). Morphological analysis shows no major differences between the t(15;17)(q24;q21) positive group and the PML-RARA positive patients without t(15;17)(q24;q21). Three way translocations demonstrated that the crucial event lies on der(15), which receives the end part of chromosome 17.
A subset of patients, often with morphological features resembling APL, show variant translocations involving RARA (17q21). These variant fusion partners include ZBTB16 (previously known as PLZF at 11q23) in t(11;17)(q23;q21), NPM1 at 5q35 in t(5;17)(q32;q12), and NUMA1 at 11q13 in t(11;17)(q13;q21) ID: 1126> and STAT5B at 17q11.2 in dup(17)(q12q21). Some APL variants, including t(11;17)(q23;q12) with ZBTB16-RARA and cases with STAT5B-RARA fusions are resistant to ATRA.
Mutations involving FLT3 occur in 34-45% of APL.
Gene name
PML (promyelocytic leukemia)
Location
15q24.1
Dna rna description
Numerous splices in 3.
Protein description
Nuclear protein; contains zinc fingers and a leucine zipper; transcription factor.
Gene name
RARA (Retinoic acid receptor, alpha)
Location
17q21.2
Protein description
Wide expression; nuclear receptor; binds specific DNA sequences: HRE (hormone response elements); ligand and dimerization domain; role in growth and differentiation.

Result of the Chromosomal Anomaly

Atlas Image
PML and RARA breakpoints in the t(15;17) / 5 PML - 3 RARA fusion gene - Courtesy Hossein Mossafa.

Description

Variable breakpoint in PML between intron 3 and exon 7a; constant breakpoint in intron 2 of RARa.

Transcript

5 PML -3 RARa transcript is found in all cases, and 5 RARa - 3 PML transcript is detected in 2/3 of cases.
Atlas Image

Description

Variable, as breakpoints in PML are variable; e.g.: 932 amino acids; 103 kDa; N-term PML, with the DNA binding and the dimerization domains fused to most of RARa with the DNA and retinoid binding regions.

Oncogenesis

Abnormal retinoic acid receptor with a dominant effect over RARa, antagonizing differentiation.

Highly cited references

Pubmed IDYearTitleCitations
322952682020Classic and Variants APLs, as Viewed from a Therapy Response.173
321826842020Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene.172
385035022024Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities.144
227782762012The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.134
373889252023Biomolecular Condensates in Myeloid Leukemia: What Do They Tell Us?131
316353292019Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies.126
339579992021Current views on the genetic landscape and management of variant acute promyelocytic leukemia.121
380610172023Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein.112
212580472011Dynamics of epigenetic modifications in leukemia.104
243442432013Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia.103
238477622013PML, SUMOylation, and Senescence.100
380989672023Different Isoforms of PML-RARA Chimeric Protein in Patients with Acute Promyelocytic Leukemia: Survival Analysis per Demographic Characteristics, Clinicohematological Parameters, and Cytogenetic Findings.90
386484852024PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.86
397663022024Rapid Detection of PML::RARA Fusions in Acute Promyelocytic Leukemia: CRISPR/Cas9 Nanopore Sequencing with Adaptive Sampling.83
376559652023Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function.78
341938152021Acute promyelocytic leukemia current treatment algorithms.77
280176142017FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N(6)-Methyladenosine RNA Demethylase.74
385394952024Acute Promyelocytic Leukemia: Review of Complications Related to All-Trans Retinoic Acid and Arsenic Trioxide Therapy.74
320242322020Advances in Pediatric Acute Promyelocytic Leukemia.73
287948652017Recent advances in acute promyelocytic leukaemia.71
228178902012The origin and evolution of mutations in acute myeloid leukemia.69
368805962023The p97/VCP segregase is essential for arsenic-induced degradation of PML and PML-RARA.67
341251732021Tumor suppressor function of Gata2 in acute promyelocytic leukemia.64
319059962019PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells.52
265958132016PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia.51
150965412004PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation.48
367596202023Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia.43
383041772024Acute promyelocytic leukemia with PML/RARA (bcr1, bcr2 and bcr3) transcripts in a pediatric patient.41
251267242014MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia.41
230563332012Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice.40
364523492022Analytical study of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1(p210) , and KMT2-MLLT3 in Mexican children with acute myeloid leukemia: A multicenter study of the Mexican interinstitutional group for the identification of the causes of childhood leukemia (MIGICCL).39
213642832011PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice.38
276267032016PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity.37
259446862015Absolute quantification of the pretreatment PML-RARA transcript defines the relapse risk in acute promyelocytic leukemia.36
302899022018Identification of the novel deletion-type PML-RARA mutation associated with the retinoic acid resistance in acute promyelocytic leukemia.32
224066212012The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA.32
251191062014The DNA binding property of PML/RARA but not the integrity of PML nuclear bodies is indispensable for leukemic transformation.31
336144842020Oral Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Acute Promyelocytic Leukemia.31
220907132011Characterization of cryptic rearrangements, deletion, complex variants of PML, RARA in acute promyelocytic leukemia.26
323235842020Clinical significance of increased PML-RARa transcripts after induction therapy for acute promyelocytic leukaemia.22
280286572017PML-RARA mutations confer varying arsenic trioxide resistance.14
342309152021PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?10
336500612022The PML-RARA fusion is not detectable in historical blood samples of acute promyelocytic leukaemia patients.10
355729172022Cytogenetically cryptic PML::RARA fusion in acute promyelocytic leukemia: Testing strategies in the modern era.10
364043342022Adefovir dipivoxil inhibits APL progression through degradation of the oncoprotein PML-RARA.8
292458952017Progress and criticalities in the management of acute promyelocytic leukemia.7
315557232019Educational Case: Acute Promyelocytic Leukemia With PML-RARA.6
373143042023HNRNPC-RARA Fusion Gene in a Case with Acute Promyelocytic Leukemia Lacking PML-RARA Rearrangement Presenting with Abundant Hemophagocytosis.3
324731062020Genotypic and Phenotypic Characteristics of Acute Promyelocytic Leukemia Translocation Variants.0
390178502024Function of PML-RARA in Acute Promyelocytic Leukemia.0
358540962022A novel RARA-SNX15 fusion in PML-RARA-positive acute promyelocytic leukemia with t(11;17;15)(q13;q21.2;q24.1).0
13378471992RARA and PML genes in acute promyelocytic leukemia.0
375989132023PML/RARa leukemia induced murine model for immunotherapy evaluation.0
220562432012Curing APL through PML/RARA degradation by As2O3.0
198088682009Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure.0
358824082022MicroRNA-125b Accelerates and Promotes PML-RARa-driven Murine Acute Promyelocytic Leukemia.0
252583432014Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation.0
305369582019PML/RARA inhibits expression of HSP90 and its target AKT.0
201558402010Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia.0
304214752019Identification and monitoring of atypical PML/RARA fusion transcripts in acute promyelocytic leukemia.0
265373012016Varying responses of PML-RARA with different genetic mutations to arsenic trioxide.0
339834182021bcr3 PML-RARA: short fusion, small blasts!0
291365032017Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure.0
312811492019[Genetic abnormalities in AML].0
14860331992Diagnosis of acute promyelocytic leukaemia by RT-PCR: detection of PML-RARA and RARA-PML fusion transcripts.0
206093552010PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.0
356398302022Typical, atypical and cryptic t(15;17)(q24;q21) (PML::RARA) observed in acute promyelocytic leukemia: A retrospective review of 831 patients with concurrent chromosome and PML::RARA dual-color dual-fusion FISH studies.0
157103272005A sumoylation site in PML/RARA is essential for leukemic transformation.0
361125052022How retinoic acid and arsenic transformed acute promyelocytic leukemia therapy.0
270305462016PCGF2 negatively regulates arsenic trioxide-induced PML-RARA protein degradation via UBE2I inhibition in NB4 cells.0
244335072013Novel treatment of acute promyelocytic leukemia: As₂O₃, retinoic acid and retinoid pharmacology.0
262943322015Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients.0
263746322016PML-RARa modulates the vascular signature of extracellular vesicles released by acute promyelocytic leukemia cells.0
334287992021Identification of a novel TNRC18-RARA fusion in acute promyelocytic leukemia lacking t(15;17)(q24;q12)/PML-RARA.0
310859082019An Atypical PML-RARA Rearrangement Resulting from Submicroscopic Insertion of the RARA Gene at the PML Locus with Novel Breakpoints within PML Exon 7b and RARA Exon 3.0
300265702018Molecular remission as a therapeutic objective in acute promyelocytic leukemia.0
303055032018[State-of-the-art treatment of acute promyelocytic leukemia].0
295508282017A Paediatric Acute Promyelocytic Leukaemia Patient Harbouring a Cryptic PML-RARA Insertion due to a Complex Structural Chromosome 17 Rearrangement.0
280255812017PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.0
344053932021PML-RARA transcript levels at the end of induction therapy are associated with prognosis in non-high-risk acute promyelocytic leukaemia with all-trans retinoic acid plus arsenic in front-line therapy: long-term follow-up of a single-centre cohort study.0
78582481995Acute promyelocytic leukemia cases with nonreciprocal PML/RARa or RARa/PML fusion genes.0
312049262019[Detection of Exosomal PML-RARA Fusion Gene Expression Level by Droplet Digital PCR].0
226925092012The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling.0
86740461996Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway.0
176134342007RXR is an essential component of the oncogenic PML/RARA complex in vivo.0
165025812006Diagnosis and monitoring of PML-RARA-positive acute promyelocytic leukemia by qualitative RT-PCR.0
223837942012CEBPE activation in PML-RARA cells by arsenic.0
88190701996Variant and masked translocations in acute promyelocytic leukemia.0
96245361998In vitro response to all-trans retinoic acid of acute promyelocytic leukemias with nonreciprocal PML/RARA or RARA/PML fusion genes.0
281836802019Diagnosis of variant RARA translocation using standard dual-color dual-fusion PML/RARA FISH probes: An illustrative report.0
106737422000A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities.0
109923012000PML-RARA fusion transcripts in irradiated and normal hematopoietic cells.0
326021272020PML-RARA monitoring in newly diagnosed acute promyelocytic leukemia treated with an entirely oral chemotherapy-free postremission approach: A multiple institution experience.0
329094802020Cytogenetically cryptic and fish negative PML/RARA rearrangement in acute promyelocytic leukemia detected by RT-PCR.0
246734202014PML-RARA fusion resulting from a cryptic insertion of RARA gene into PML gene without the reciprocal RARA-PML fusion: clinical, cytogenetic, and molecular characterization and prognosis.0
171349652006Gene expression regulation and cancer.0
382945342024Identification of a novel fusion gene, RARA::ANKRD34C, in acute promyelocytic leukemia.0
125507692002RARA fluorescence in situ hybridization overcomes the drawback of PML/RARA fluorescence in situ hybridization in follow-up of acute promyelocytic leukemia.0
278990392017Sensitive monitoring of acute promyelocytic leukemia by PML-RARA DNA Q-PCR.0
192731552009PML nuclear bodies in the pathogenesis of acute promyelocytic leukemia: active players or innocent bystanders?0

Article Bibliography

Pubmed IDLast YearTitleAuthors
18480171991Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus.Alcalay M et al
17970831991Cytogenetic studies in acute promyelocytic leukemia: a survey of secondary chromosomal abnormalities.Berger R et al
22185001990Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17.Borrow J et al
77877531995Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy: The European experience. European APL Group.Fenaux P et al
172170412007Treatment of acute promyelocytic leukemia by retinoids.Fenaux P et al
13141661992Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia.Pandolfi PP et al
85157901993Acute promyelocytic leukemia.Warrell RP Jr et al
21708501990The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.de Thé H et al

Summary

Fusion gene

PML/RARA PML (15q24.1) RARA (17q21.2) M ins(15;17)(q22;q21q21) ins(17;15)(q21;q22q22) ins(4;15)(q21;q?q22)t(15;17)(q22;q21) t(11;17)(q23;q21) t(11;17;15)(q13;q21;q22) t(13;17;15)(p13;q21;q22) t(15;17)(q22;q21) t(15;17;16)(q22;q21;q13) t(15;17;18)(q22;q21;q12) t(15;17;19)(q22;q21;q13) t(1;17;15)(p32;q21;q22) t(3;17;15)(p21;q21;q22) t(3;17;15)(q27;q21;q22) t(5;17)(q35;q21) t(5;17;15)(q11;q21;q22) t(5;17;15)(q14;q21;q22) t(5;17;15)(q35;q21;q22) t(6;17;15)(p21;q21;q22) t(7;17;15)(q22;q21;q22) t(8;17;15)(q22;q21;q22) t(8;17;15)(q24;q21;q22) t(9;17;15)(q31;q21;q22)|PML/RARA PML (15q24.1) RARA (17q21.2) TF LAML|PML/RARA PML (15q24.1) RARA (17q21.2) TIC

Note

The translocation, formerly known as t(15;17)(q22;q21) or t(15;17)(q22;q12), has been renamed t(15;17)(q24;q21), since PML is located in chromosome band 15q24, and RARA in chromosome band 17q21.
Atlas Image
t(15;17)(q24;q21) G- banding (left) - 2 top left: Courtesy Jean-Luc Lai and Alain Vanderhaegen, 2 bottom left: Courtesy Roland Berger ; center left and right - Courtesy Adriana Zamecnikova; R-banding (right) - top: Editor, middle - Courtesy Christiane Charrin, bottom - Courtesy Roland Berger. ider(17)t(15;17) - Courtesy Adriana Zamecnikova. Fluorescence in situ hybridization with the LSI PML/RARA dual colour translocation probe (Abbott Molecular, US) fusion red-green signal on der(15), the most frequently encountered FISH pattern in patients (A). Atypical fusion patterns include the presence of fusion signal on der(17) chromosome (B) and the presence of derivative 17 chromosome that result from the formation of derivative isochromosome ider(17)t(15;17) resulting in p53 deletion (C,D) - Courtesy Adriana Zamecnikova.

Citation

Pino J. Poddighe ; Pino J. Poddighe

t(15;17)(q24;q21) PML/RARA

Atlas Genet Cytogenet Oncol Haematol. 2016-03-01

Online version: http://atlasgeneticsoncology.org/haematological/1035/t(15;17)(q24;q21)-pml-rara

Historical Card

1998-04-01 t(15;17)(q24;q21) PML/RARA by  Christine Chomienne,Jean-Loup Huret 

Laboratoire de Biologie Cellulaire Hématopoïétique, EP-107 CNRS, Institut d Hématologie, Hôpital Saint Louis, Centre Hayem, Paris, France