M3/M3v acute myeloid leukemia (AML M3/M3v)
Acute promyelocytic leukemia (APL)
Acute promyelocytic leukemia (APL) PML/RARA

2017-04-01   Marina Lafage , Marina Lafage 

1.Department of Genetics, Aix-Marseille University, Marseille; marina.lafage@ap-hm.fr (ML), Service dHistologie-Embryologie-Cytogénétique, Unité de Cytogénétique Onco-Hématologique, Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France; franck.viguie@aphp.fr.
2.MLL Münchner Leukümielabor GmbH, Max-Lebsche-Platz 31, 81377 München, Germany

Abstract

Review on Acute promyelocytic leukemia, with data on clinics and the genes involved.

Clinics and Pathology

Epidemiology

Rare: 5 - 8 % of AML, incidence higher in Spain, Italy and Latinos; occurs at any age, predominantly adults in mid-life.
Account for approximatively. 5% of treatment related leukemias (t-AML); 5-22% of APL are t-APL, mostly after breast cancer treated by epirubicine or mitoxantrone (chemotherapy targeting topo 2 isomerase); short-delayed (median inferior to 3 years) ; favorable prognosis among t-AML: benefit from ATRA-ATO treatment thus avoiding anthracyclins (reviewed in Lo Coco F, 2013).

Clinics

Low WBC in AML M3, high WBC in AML M3v; frequently associated with disseminated intravascular coagulation (DIC) and hyperfibrinolysis which are the main factors of immediate bad prognosis and death when diagnostic and treatment are delayed.
Biological and clinical data favour a crucial role of the leukemic cells in the development of the coagulopathy which is a multifactorial event, involving DIC and primary hyperfibrinolysis (Mantha et al., 2016).

Cytology

The cytomorphology of APL blasts is obviously different in the two subtypes: in AML M3, the abnormal promyelocytes show a heavy granulation and bundles of Auer rods; in AML M3v blasts have a non- or hypogranular cytoplasm or contain fine dustlike cytoplasmic granules that may not be apparent by light microscopy. Furthermore, M3v blasts show a typical bilobed nuclear configuration. This latter morphologic phenotype, together with missing granulation, often resulted in the misleading diagnosis of acute monocytic or myelo-monocytic leukemia before the cytogenetic correlation of both AML M3 and M3v with t(15;17)(q24;q21) was observed. AML M3v accounts for approximately 1/3 of APL cases.

Treatment

Previous chemotherapies which associated anthracyclines and cytosine arabinoside allowed long-lived remission in less than 50% of patients. From 1985 retinoic acid (RA) isomers were introduced with success as differentiation agents in several series of APL patients. The first molecule tested was 13-cis RA. In parallel all-trans RA (ATRA) showed a quite better efficacy. Then another molecule, arsenic trioxide (ATO), acting on differentiation and apoptosis, was tested with good results. With the current treatments, involving anthracycline chemotherapy associated with ATRA and/or ATO, a long-lived remission is obtained in more than 90% of cases, and bone marrow transplantation has been restricted to the sole cases of first relapse. Particularly the introduction of ATRA and/or ATO therapy at diagnosis, has largely reduced the rate of early death due to the coagulopathy associated with APL first stage (Wang Z-Y and Chen Z, 2008). Patients with low WBC (less than 10G/L) can be treated at diagnosis with ATRA and ATO thus avoiding the toxicity of chemotherapy especially anthracyclins (Lo Coco et al, NEJM, 2013).
To be noted that some variant translocations, i.e. t(11;17) with ZBTB1/RARA fusion and der(17) with STAT5B/RARA fusion do not respond to ATRA and ATO therapy, consequently their prognosis is quite more pejorative.

Evolution

APL PML/RARA have to be monitored by RQ-PCR on bone marrow samples every 3 months after diagnosis for 18 months as patients with molecular relapse can benefit from preemptive therapy . Patients with hyperleucocytosis at diagnosis ( more than 10 G/L WBC) or slow responding to treatment more especially benefit from this survey .(reviewed in Grimade D et al, BPRCH, 2014)

Prognosis

Adverse prognosis factors
  • High WB (more than 10 G/L).
  • The previously reported FLT3- internal tandem duplication (ITD). PROGNOSIS
  • Bad prognosis value is correlated with hyperleucocytosis asit is the case for the bcr3 molecular breakpoint and the M3v form.
  • Bleeding episodes.
  • Cytogenetics

    Cytogenetics morphological

    t(15;17)(q24.1;q21.2) leading to a PML (promyelocytic leukaemia)/RARA(retinoic acid receptor α) on der(15) and RARA/PML on der(17) rearrangements at the molecular level.
    Complex translocations involving one or more chromosomes in addition to 15 and 17 are found in 2-5% of cases with PML/RARA rearrangement.
    Cytogenetically cryptic PML/RARA rearrangements are observed in 2-3% of APL cases.
    Cases lacking PML/RARA rearrangement account for less than 2% M3/M3v AML cases and mainly involve RARA with partner genes different from PML (Grimwade D et al, Blood 2000).

    Cytogenetics molecular

    When karyotype fails to give an informative response, either for absence or poor quality metaphases or in case of complex or cryptic rearrangement, FISH analysis may be useful to validate PML/RARA fusion and initiate without delay or maintain specific APL therapy.
    Furthermore as cytogenetic diagnosis is urgent, FISH analysis can be performed urgently in parallel with karyotype analysis, preferably on cultured and fixed cells.
    Among cryptic rearrangements, they are mainly insertions:
  • mainly insertion of 3RARA into the PML gene: ins(15;17)(q24;q21q21)
  • but insertions of 5PML into RARA can also be seen: ins(17;15)(q21;q24q24)
  • Probes

    Different type of probes are commercially available:
  • PML/RARA fusion probes leading to either double or single fusion signals in positive cells
  • RARA break-apart probes leading to separated 5RARA and 3RARA signals signal in positive cells but failing to identify the RARA partner in nuclei. They identify the partner chromosome band if metaphases are present on the hybridized slide.
    Among these probes, some are less informative in case of cryptic insertions which accounts for approximately 5% of APL cases
  • Very large probes can fail to detect very small insertions.
  • RARA probes cannot detect PML insertions.
  • Flanking probes can fail to detect very small insertions.
    The choice of informative probes has to take into account the probe maps and the critical fusion gene to be detected (PML/RARA rather than RARA/PML), thus covering 5PML and 3RARA. In order to obtain an optimal diagnosis (rapid and informative) multiple slides, each with a different type of probe can be hybridized. Furthermore, small insertions are easier to be detected on metaphases rather than on nuclei and the chromosomal location of the specific signals is very helpful for diagnosis. .
    Other diagnosis tools are:
    PML immunofluorescence leading to a specific microspeckled pattern in nuclei of PML/RARA positive cases, related to the disruption of PML nuclear bodies.
    PML/RARA RT-PCR analysis, very specific and sensitive, mandatory at diagnosis.
  • Additional anomalies

    (ACA) are observed in 35-45% of cases at diagnosis (62% at relapse), most frequent: +8(or trisomy 8q), del(9q), ider(17)(q10)t(15;17) or del(17p)
    Classically, ACA do not impact the prognosis, however the loss of one copy of TP53 gene generated by ider(17q) or del(17p) could have a prognostic value. Complex karyotype at diagnosis, defined as ≥ 2 anomalies in addition to t(15;17), could be associated too with a reduced overall survival (Poiré X et al., 2014).

    Variants

    Approximately 1-2% of M3/M3v AML cases harbor a variant translocation which fuses RARA with an other partner gene than PML (Grimwade D et al. 2000; Redner RL, 2002):
  • t(11;17)(q23;q21) ZBTB16/RARA (also named PLZF/RARA), is the most frequent
  • t(5;17)(q23;q21) NPM1/RARA,
  • t(11;17)(q13;q21) NUMA1/RARA,
  • der(17) STAT5B /RARA,
  • der(17) PRKAR1A /RARA,
  • t(X;17)(p11;q12) BCOR /RARA,
  • t(4;17)(q12;q21) FIP1L1 /RARA
  • t(1;17)(p34;q21) IRF2BP2 /RARA
  • t(2;17)(q32;q21) NABP1 /RARA
  • t(3;17)(q26;q21) TBL1XR1 /RARA
  • t(7;17)(q11;q21) GTF2I /RARA
    The cases with variant translocation have initially been reported as having APL morphology. However, morphological differences exist. Clinically important is that APL variant with t(5;17)(q12;q12) NPM1/RARA, respond to ATRA, while M3/M3v AML with t(11;17)(q23;q12) ZBTB16/RARA or der(17) STAT5B/RARA do not respond to ATRA or ATO.
  • Genes Involved and Proteins

    Gene name
    PML (promyelocytic leukemia)
    Location
    15q24.1
    Dna rna description
    9 exons, 53 kb; alternative splicing on side of the transcript coding for the c-terminal part of the protein, leads to 6 nuclear and 1 cytoplasmic isoforms.
    Protein description
    The PML protein is a tumor suppressor implicated in a wide variety of cellular activities: apoptosis, differentiation, genome stability. It has 3 zinc binding domains, BB1 (b-box1) and BB2 (b-box2) regions, and a coil-coiled region (CC). It contains also a C-terminal SUMO interaction motif (SIM) and 3 lysine residues able to be modified by SUMOylation.
    PML organises and is located in PML-nuclear bodies (PML-NBs) which are 0.2 to 1.0 m organelles, mainly located in the nucleus of many cell types. Their number varies from 5 to 30 per nucleus, according to the cell cycle and the differentiation stage. PML-NBs are actively involved in transcriptional regulation of a number of loci active in cell growth and differentiation. Proteins are stored or sequestered inside PML-NBs, until they are required. PML-NBs mediate protein modifications such as SUMOylation, acetylation, ubiquitination and phosphorylation (Bernardi and Pandolfi, 2007).
    Gene name
    RARA (Retinoic acid receptor, alpha)
    Location
    17q21.2
    Protein description
    RARα protein is a member of nuclear steroid receptors and it presents homologies with nuclear receptors of vitamin D and thyroid hormone. It contains 2 zinc finger motifs which constitute the domain of linkage to the DNA (DBD, DNA binding domain). This link needs the formation of a heterodimer with the cofactor RXRα to be stable.

    Result of the Chromosomal Anomaly

    Description

    t(15;17) leads to 2 fusion genes PML/RARA and RARA/PML. The latter is not critical; indeed it is lacking in 30% of cases either due to a submicroscopic deletion or, less frequently, to a mechanism of insertion. Variant or alternative translocations all involve RARA with another partner than PML; no variants are known involving PML with a partner different from RARA.The PML/RARA fusion oncoprotein is expressed in 100% of APL cases with t(15;17) and is crucial for the leukemic phenotype, while RARA/PML is expressed in no more than 80-90% of cases and probably plays a secondary role.
    PML/RARA is able to homodimerise via the coiled-coil domain of PML, forming a complex which binds to the DNA on RARE sites. It acts as a dominant-negative transcriptional repressor of both target and non-target genes of retinoic acid. The main consequence is the arrest of myeloid cells differentiation at the promyelocytic stage. To achieve the gene silencing process, PML/RARA recruits various nuclear receptors with co-repressor properties, out of which RXRα, polycomb complex or DAXX (ZHU et al.; 2007, Lo-Coco and Hasan, 2014).

    Highly cited references

    Pubmed IDYearTitleCitations
    355444582022A short report of novel RARG-HNRNPM fusion gene in resembling acute promyelocytic leukemia.0
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    356927862022Case Report: Extramedullary Acute Promyelocytic Leukemia: An Unusual Case and Mini-Review of the Literature.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
    355729172022Cytogenetically cryptic PML::RARA fusion in acute promyelocytic leukemia: Testing strategies in the modern era.0
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    354496102022Intracranial Hemorrhage Secondary to Newly Diagnosed Acute Promyelocytic Leukemia: A Cautionary Tale.0
    350921192022LncSIK1 enhanced the sensitivity of AML cells to retinoic acid by the E2F1/autophagy pathway.1
    346684512022Value of measurable residual disease monitoring in patients with acute promyelocytic leukemia in the era of frontline 'chemotherapy-free' therapy.0
    345463302022Interdisciplinary Quality Improvement Led by the Molecular Pathology Laboratory Expedites Diagnosis of Acute Promyelocytic Leukemia.0
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    352511312022Fusion Gene Detection Using Whole-Exome Sequencing Data in Cancer Patients.0
    350656802022Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies.2
    346739342022A novel NUP98-JADE2 fusion in a patient with acute myeloid leukemia resembling acute promyelocytic leukemia.0
    346257942022Metabolic adaptation drives arsenic trioxide resistance in acute promyelocytic leukemia.1
    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
    349450032021PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.1
    339430022021FACSorting help to analyze a rare case of acute myeloid leukemia with concurrent AML1-ETO and PML-RARA.0
    345347392021Identification of variant APL translocations PRKAR1A-RARα and ZBTB16-RARα (PLZF-RARα) through the MI-ONCOSEQ platform.1
    342361082021Novel MLL/KMT2A-MON2 fusion in a child with therapy-related acute myeloid leukemia after treatment for acute promyelocytic leukemia.0
    347952152021Genetic fusions favor tumorigenesis through degron loss in oncogenes.1
    344328672021Torque teno mini virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion.1
    347443412021An Outcome Analysis of Childhood Acute Promyelocytic Leukemia Treated with Atra and Arsenic Trioxide, and Limited Dose Anthracycline.1
    343107402021RBCK1-TRIB3 decelerated the progression of acute promyelocytic leukemia.0
    342543142021A novel HNRNPC-RARA fusion in acute promyelocytic leukaemia lacking PML-RARA rearrangement, sensitive to venetoclax-based therapy.2
    341251732021Tumor suppressor function of Gata2 in acute promyelocytic leukemia.1
    342988582021Correction: Liquori et al. Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers 2020, 12, 624.0
    342497382021Myeloid Sarcoma Type of Acute Promyelocytic Leukemia With a Cryptic Insertion of RARA Into FIP1L1: The Clinical Utility of NGS and Bioinformatic Analyses.1
    342309152021PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?1
    342681252021Case Report: Very Late, Atypical Extra-Medullary Relapse in a Patient With Acute Promyelocytic Leukemia (APL) Rescued With a Transplant-Free Approach.0
    341938152021Acute promyelocytic leukemia current treatment algorithms.4
    341694212021All-trans Retinoic Acid, Arsenic Trioxide, and Anthracycline-based Chemotherapy Improves Outcome in Newly Diagnosed Acute Promyelocytic Leukemia Regardless of FLT3-ITD Mutation Status.0
    327357922021No prognostic significance of normalized copy number of PML-RARA transcript at diagnosis in patients with acute promyelocytic leukemia.0
    339906602021Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features.2
    339834182021bcr3 PML-RARA: short fusion, small blasts!0
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    355444582022A short report of novel RARG-HNRNPM fusion gene in resembling acute promyelocytic leukemia.0
    356153202022Has Hematopoietic Stem Cell Transplantation a Role in the Treatment of Children and Adolescents with Acute Promyelocytic Leukemia?0
    356927862022Case Report: Extramedullary Acute Promyelocytic Leukemia: An Unusual Case and Mini-Review of the Literature.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
    355729172022Cytogenetically cryptic PML::RARA fusion in acute promyelocytic leukemia: Testing strategies in the modern era.0
    347257112022Acute Promyelocytic Leukemia with a BCR-ABL1 Rearrangement in a Minor Clone.0
    354496102022Intracranial Hemorrhage Secondary to Newly Diagnosed Acute Promyelocytic Leukemia: A Cautionary Tale.0
    350921192022LncSIK1 enhanced the sensitivity of AML cells to retinoic acid by the E2F1/autophagy pathway.1
    346684512022Value of measurable residual disease monitoring in patients with acute promyelocytic leukemia in the era of frontline 'chemotherapy-free' therapy.0
    345463302022Interdisciplinary Quality Improvement Led by the Molecular Pathology Laboratory Expedites Diagnosis of Acute Promyelocytic Leukemia.0
    336500612022The PML-RARA fusion is not detectable in historical blood samples of acute promyelocytic leukaemia patients.0
    352511312022Fusion Gene Detection Using Whole-Exome Sequencing Data in Cancer Patients.0
    350656802022Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies.2
    346739342022A novel NUP98-JADE2 fusion in a patient with acute myeloid leukemia resembling acute promyelocytic leukemia.0
    346257942022Metabolic adaptation drives arsenic trioxide resistance in acute promyelocytic leukemia.1
    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
    349450032021PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.1
    339430022021FACSorting help to analyze a rare case of acute myeloid leukemia with concurrent AML1-ETO and PML-RARA.0
    345347392021Identification of variant APL translocations PRKAR1A-RARα and ZBTB16-RARα (PLZF-RARα) through the MI-ONCOSEQ platform.1
    342361082021Novel MLL/KMT2A-MON2 fusion in a child with therapy-related acute myeloid leukemia after treatment for acute promyelocytic leukemia.0
    347952152021Genetic fusions favor tumorigenesis through degron loss in oncogenes.1
    344328672021Torque teno mini virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion.1
    347443412021An Outcome Analysis of Childhood Acute Promyelocytic Leukemia Treated with Atra and Arsenic Trioxide, and Limited Dose Anthracycline.1
    343107402021RBCK1-TRIB3 decelerated the progression of acute promyelocytic leukemia.0
    342543142021A novel HNRNPC-RARA fusion in acute promyelocytic leukaemia lacking PML-RARA rearrangement, sensitive to venetoclax-based therapy.2
    341251732021Tumor suppressor function of Gata2 in acute promyelocytic leukemia.1
    342988582021Correction: Liquori et al. Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers 2020, 12, 624.0
    342497382021Myeloid Sarcoma Type of Acute Promyelocytic Leukemia With a Cryptic Insertion of RARA Into FIP1L1: The Clinical Utility of NGS and Bioinformatic Analyses.1
    342309152021PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?1
    342681252021Case Report: Very Late, Atypical Extra-Medullary Relapse in a Patient With Acute Promyelocytic Leukemia (APL) Rescued With a Transplant-Free Approach.0
    341938152021Acute promyelocytic leukemia current treatment algorithms.4
    341694212021All-trans Retinoic Acid, Arsenic Trioxide, and Anthracycline-based Chemotherapy Improves Outcome in Newly Diagnosed Acute Promyelocytic Leukemia Regardless of FLT3-ITD Mutation Status.0
    327357922021No prognostic significance of normalized copy number of PML-RARA transcript at diagnosis in patients with acute promyelocytic leukemia.0
    339906602021Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features.2
    339834182021bcr3 PML-RARA: short fusion, small blasts!0
    339579992021Current views on the genetic landscape and management of variant acute promyelocytic leukemia.4
    338516472021Cytogenetics and FISH negative cryptic acute promyelocytic leukemia with CD56 expression.0
    337893752021[Application of transcriptome sequencing and fusion genes analysis in the diagnosis of myeloid leukemia with normal karyotype].1
    332578642021Readfish enables targeted nanopore sequencing of gigabase-sized genomes.29
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    336144842020Oral Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Acute Promyelocytic Leukemia.2
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    339736432021Clinicopathological Evaluation of Acute Leukemias in a Tertiary Care Hospital: A Cross-Sectional Study.0
    334888392021Bronchoalveolar lavage fluid review in acute promyelocytic leukemia differentiation syndrome.0
    354593862021Preleukemic fusion genes typical for acute myeloid leukemia.0
    334732642021Acute myeloid leukemia with CPSF6-RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration.2
    333037092020Changing the frequency and spectra of chromosomal aberrations in Korean patients with acute leukemia in a tertiary care hospital.0
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    324731062020Genotypic and Phenotypic Characteristics of Acute Promyelocytic Leukemia Translocation Variants.4
    334474732020Differentiation Syndrome, a Side Effect From the Therapy of Acute Promyelocytic Leukemia.1
    332049992020Identification of Fusion Gene Breakpoints is Feasible and Facilitates Accurate Sensitive Minimal Residual Disease Monitoring on Genomic Level in Patients With PML-RARA, CBFB-MYH11, and RUNX1-RUNX1T1.0
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    329531852020PML-RARA Fusion Transcripts Detectable 8 Months prior to Promyelocytic Blast Crisis in Chronic Myeloid Leukemia.0
    325243092020Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.0
    328476102020The diagnostic power of CD117, CD13, CD56, CD64, and MPO in rapid screening acute promyelocytic leukemia.0
    323235842020Clinical significance of increased PML-RARa transcripts after induction therapy for acute promyelocytic leukaemia.0
    328238552020Emerging Cancer Epigenetic Mechanisms Regulated by All-Trans Retinoic Acid.5
    326021082020Successful Treatment of Therapy-related Acute Promyelocytic Leukemia with All-trans-retinoic acid Following Epirubicin for Hepatocellular Carcinoma and Docetaxel and Pembrolizumab Therapies for Lung Carcinoma: A Triple Malignancy Case.0
    325529382020[Analysis of Genomic Landscape in Patients with Acute Myeloid Leukemia].0
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    323429422020Tetraploid/near-tetraploid acute promyelocytic leukaemia with double (15;17) translocation.1
    322952682020Classic and Variants APLs, as Viewed from a Therapy Response.9
    322434112020Co-occurrence of PML-RARA gene fusion, chromosome 8 trisomy, and FLT3 ITD mutation in a young female patient with de novo acute myeloid leukemia and early death: A CARE case report.0
    318096702020Characterization of a cryptic PML-RARA fusion by mate-pair sequencing in a case of acute promyelocytic leukemia with a normal karyotype and negative RARA FISH studies.1
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    322151872020Acute promyelocytic leukemia (APL): a review of the literature.17
    321826842020Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene.23
    320339282020Prognostic Significance of bcr-1 and bcr-3 Isoforms of PML-RARA and FLT3-ITD in Patients With Acute Promyelocytic Leukemia.1
    321850692020Acute promyelocytic leukemia presenting with atypical basophils.1
    321172722020Neoantigens in Hematologic Malignancies.12
    320242322020Advances in Pediatric Acute Promyelocytic Leukemia.9
    331625102020[Clinical significance of MRD in AML].0
    331624502020[Microgranular-type acute promyelocytic leukemia with weak myeloperoxidase staining: difficulty of morphological diagnosis].0
    329080492020[Therapy-related acute promyelocytic leukemia developing during chemotherapy for thymic carcinoma].0
    318297592020Report of a new six-panel flow cytometry marker for early differential diagnosis of APL from HLA-DR negative Non-APL leukemia.6
    332986492020[Therapy-related acute promyelocytic leukemia with complex karyotype accompanied by cryptic PML/RARA on chromosome 15 by metaphase FISH].0
    321476082020[Leukemic cell kinetics of APL with a novel complex variant t (12;17;15)(p13;q21;q22)].1
    319059962019PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells.1
    317074162019Overall survival of adult acute myeloid leukemia based on cytogenetic and molecular abnormalities during 5 years in a single center study.0
    313509302019Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1.5
    316253672019A Rare Morphology Resembling APL with t (11;12) (p15;q13) in Acute Myeloid Leukemia: Case Report and Literature Review.1
    313437372019Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction.4
    316353292019Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies.25
    314464582019Clinician-friendly reports of molecular measurable residual disease monitoring in acute promyelocytic leukemia.0
    315557232019Educational Case: Acute Promyelocytic Leukemia With PML-RARA.0
    314470652019Characterization of a rarely reported STAT5B/RARA gene fusion in a young adult with newly diagnosed acute promyelocytic leukemia with resistance to ATRA therapy.3
    315791352019A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms.1
    310287442019Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders.12
    308061062019Myeloid neoplasm with eosinophilia and PCM1-JAK2 associated with acute promyelocytic leukemia with PML-RARA.1
    314475642019A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion; and literature review.7
    314314732019A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells.4
    313962782019HDAC and HMT Inhibitors in Combination with Conventional Therapy: A Novel Treatment Option for Acute Promyelocytic Leukemia.3
    313719842019t(15; 17) associated with primary myelofibrosis: a case report of an unusual clinical presentation and diagnostic dilemma.1
    308099812019The Incidence and Immunophenotypic and Genetic Features of JL1 Expressing Cells and the Therapeutic Potential of an Anti-JL1 Antibody in De Novo Pediatric Acute Leukemias.1
    355444582022A short report of novel RARG-HNRNPM fusion gene in resembling acute promyelocytic leukemia.0
    356153202022Has Hematopoietic Stem Cell Transplantation a Role in the Treatment of Children and Adolescents with Acute Promyelocytic Leukemia?0
    356927862022Case Report: Extramedullary Acute Promyelocytic Leukemia: An Unusual Case and Mini-Review of the Literature.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
    355729172022Cytogenetically cryptic PML::RARA fusion in acute promyelocytic leukemia: Testing strategies in the modern era.0
    347257112022Acute Promyelocytic Leukemia with a BCR-ABL1 Rearrangement in a Minor Clone.0
    354496102022Intracranial Hemorrhage Secondary to Newly Diagnosed Acute Promyelocytic Leukemia: A Cautionary Tale.0
    350921192022LncSIK1 enhanced the sensitivity of AML cells to retinoic acid by the E2F1/autophagy pathway.1
    346684512022Value of measurable residual disease monitoring in patients with acute promyelocytic leukemia in the era of frontline 'chemotherapy-free' therapy.0
    345463302022Interdisciplinary Quality Improvement Led by the Molecular Pathology Laboratory Expedites Diagnosis of Acute Promyelocytic Leukemia.0
    336500612022The PML-RARA fusion is not detectable in historical blood samples of acute promyelocytic leukaemia patients.0
    352511312022Fusion Gene Detection Using Whole-Exome Sequencing Data in Cancer Patients.0
    350656802022Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies.2
    346739342022A novel NUP98-JADE2 fusion in a patient with acute myeloid leukemia resembling acute promyelocytic leukemia.0
    346257942022Metabolic adaptation drives arsenic trioxide resistance in acute promyelocytic leukemia.1
    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
    349450032021PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.1
    339430022021FACSorting help to analyze a rare case of acute myeloid leukemia with concurrent AML1-ETO and PML-RARA.0
    345347392021Identification of variant APL translocations PRKAR1A-RARα and ZBTB16-RARα (PLZF-RARα) through the MI-ONCOSEQ platform.1
    342361082021Novel MLL/KMT2A-MON2 fusion in a child with therapy-related acute myeloid leukemia after treatment for acute promyelocytic leukemia.0
    347952152021Genetic fusions favor tumorigenesis through degron loss in oncogenes.1
    344328672021Torque teno mini virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion.1
    347443412021An Outcome Analysis of Childhood Acute Promyelocytic Leukemia Treated with Atra and Arsenic Trioxide, and Limited Dose Anthracycline.1
    343107402021RBCK1-TRIB3 decelerated the progression of acute promyelocytic leukemia.0
    342543142021A novel HNRNPC-RARA fusion in acute promyelocytic leukaemia lacking PML-RARA rearrangement, sensitive to venetoclax-based therapy.2
    341251732021Tumor suppressor function of Gata2 in acute promyelocytic leukemia.1
    342988582021Correction: Liquori et al. Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers 2020, 12, 624.0
    342497382021Myeloid Sarcoma Type of Acute Promyelocytic Leukemia With a Cryptic Insertion of RARA Into FIP1L1: The Clinical Utility of NGS and Bioinformatic Analyses.1
    342309152021PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?1
    342681252021Case Report: Very Late, Atypical Extra-Medullary Relapse in a Patient With Acute Promyelocytic Leukemia (APL) Rescued With a Transplant-Free Approach.0
    341938152021Acute promyelocytic leukemia current treatment algorithms.4
    341694212021All-trans Retinoic Acid, Arsenic Trioxide, and Anthracycline-based Chemotherapy Improves Outcome in Newly Diagnosed Acute Promyelocytic Leukemia Regardless of FLT3-ITD Mutation Status.0
    327357922021No prognostic significance of normalized copy number of PML-RARA transcript at diagnosis in patients with acute promyelocytic leukemia.0
    339906602021Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features.2
    339834182021bcr3 PML-RARA: short fusion, small blasts!0
    339579992021Current views on the genetic landscape and management of variant acute promyelocytic leukemia.4
    338516472021Cytogenetics and FISH negative cryptic acute promyelocytic leukemia with CD56 expression.0
    337893752021[Application of transcriptome sequencing and fusion genes analysis in the diagnosis of myeloid leukemia with normal karyotype].1
    332578642021Readfish enables targeted nanopore sequencing of gigabase-sized genomes.29
    338162942021Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome.0
    33841010202120(S)-ginsenoside Rh2 induces caspase-dependent promyelocytic leukemia-retinoic acid receptor A degradation in NB4 cells via Akt/Bax/caspase9 and TNF-α/caspase8 signaling cascades.1
    336143762021Tetraploid acute promyelocytic leukemia with double translocation t (15,17) PML/RARA: the first case report in Croatia and Europe.0
    336144842020Oral Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Acute Promyelocytic Leukemia.2
    335913262021Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML.3
    334287992021Identification of a novel TNRC18-RARA fusion in acute promyelocytic leukemia lacking t(15;17)(q24;q12)/PML-RARA.3
    339736432021Clinicopathological Evaluation of Acute Leukemias in a Tertiary Care Hospital: A Cross-Sectional Study.0
    334888392021Bronchoalveolar lavage fluid review in acute promyelocytic leukemia differentiation syndrome.0
    354593862021Preleukemic fusion genes typical for acute myeloid leukemia.0
    334732642021Acute myeloid leukemia with CPSF6-RARG fusion resembling acute promyelocytic leukemia with extramedullary infiltration.2
    333037092020Changing the frequency and spectra of chromosomal aberrations in Korean patients with acute leukemia in a tertiary care hospital.0
    329094802020Cytogenetically cryptic and fish negative PML/RARA rearrangement in acute promyelocytic leukemia detected by RT-PCR.1
    324731062020Genotypic and Phenotypic Characteristics of Acute Promyelocytic Leukemia Translocation Variants.4
    334474732020Differentiation Syndrome, a Side Effect From the Therapy of Acute Promyelocytic Leukemia.1
    332049992020Identification of Fusion Gene Breakpoints is Feasible and Facilitates Accurate Sensitive Minimal Residual Disease Monitoring on Genomic Level in Patients With PML-RARA, CBFB-MYH11, and RUNX1-RUNX1T1.0
    330883562020Acute Promyelocytic Leukemia After Radium-223 Exposure for Prostate Cancer in a Chemotherapy-Naïve Patient.0
    326021272020PML-RARA monitoring in newly diagnosed acute promyelocytic leukemia treated with an entirely oral chemotherapy-free postremission approach: A multiple institution experience.1
    331166342020Acute Myeloid Leukemia with NUP98-RARG Gene Fusion Similar to Acute Promyelocytic Leukemia: Case Report and Literature Review.4
    329531852020PML-RARA Fusion Transcripts Detectable 8 Months prior to Promyelocytic Blast Crisis in Chronic Myeloid Leukemia.0
    325243092020Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.0
    328476102020The diagnostic power of CD117, CD13, CD56, CD64, and MPO in rapid screening acute promyelocytic leukemia.0
    323235842020Clinical significance of increased PML-RARa transcripts after induction therapy for acute promyelocytic leukaemia.0
    328238552020Emerging Cancer Epigenetic Mechanisms Regulated by All-Trans Retinoic Acid.5
    326021082020Successful Treatment of Therapy-related Acute Promyelocytic Leukemia with All-trans-retinoic acid Following Epirubicin for Hepatocellular Carcinoma and Docetaxel and Pembrolizumab Therapies for Lung Carcinoma: A Triple Malignancy Case.0
    325529382020[Analysis of Genomic Landscape in Patients with Acute Myeloid Leukemia].0
    326956772020SERS-Based Assessment of MRD in Acute Promyelocytic Leukemia?2
    323429422020Tetraploid/near-tetraploid acute promyelocytic leukaemia with double (15;17) translocation.1
    322952682020Classic and Variants APLs, as Viewed from a Therapy Response.9
    322434112020Co-occurrence of PML-RARA gene fusion, chromosome 8 trisomy, and FLT3 ITD mutation in a young female patient with de novo acute myeloid leukemia and early death: A CARE case report.0
    318096702020Characterization of a cryptic PML-RARA fusion by mate-pair sequencing in a case of acute promyelocytic leukemia with a normal karyotype and negative RARA FISH studies.1
    324253822020Higher Level of Peripheral Blood CD34 Positive Cells Presented with Unfavorable Prognosis in Intermediate-Low Risk Acute Promyelocytic Leukemia.0
    323087402020A rare case of acute promyelocytic leukemia with ider(17)(q10)t(15;17)(q22;q21) and favorable outcome.2
    322151872020Acute promyelocytic leukemia (APL): a review of the literature.17
    321826842020Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene.23
    320339282020Prognostic Significance of bcr-1 and bcr-3 Isoforms of PML-RARA and FLT3-ITD in Patients With Acute Promyelocytic Leukemia.1
    321850692020Acute promyelocytic leukemia presenting with atypical basophils.1
    321172722020Neoantigens in Hematologic Malignancies.12
    320242322020Advances in Pediatric Acute Promyelocytic Leukemia.9
    331625102020[Clinical significance of MRD in AML].0
    331624502020[Microgranular-type acute promyelocytic leukemia with weak myeloperoxidase staining: difficulty of morphological diagnosis].0
    329080492020[Therapy-related acute promyelocytic leukemia developing during chemotherapy for thymic carcinoma].0
    318297592020Report of a new six-panel flow cytometry marker for early differential diagnosis of APL from HLA-DR negative Non-APL leukemia.6
    332986492020[Therapy-related acute promyelocytic leukemia with complex karyotype accompanied by cryptic PML/RARA on chromosome 15 by metaphase FISH].0
    321476082020[Leukemic cell kinetics of APL with a novel complex variant t (12;17;15)(p13;q21;q22)].1
    319059962019PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells.1
    317074162019Overall survival of adult acute myeloid leukemia based on cytogenetic and molecular abnormalities during 5 years in a single center study.0
    313509302019Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1.5
    316253672019A Rare Morphology Resembling APL with t (11;12) (p15;q13) in Acute Myeloid Leukemia: Case Report and Literature Review.1
    313437372019Syndromic chorioretinal coloboma associated with heterozygous de novo RARA mutation affecting an amino acid critical for retinoic acid interaction.4
    316353292019Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies.25
    314464582019Clinician-friendly reports of molecular measurable residual disease monitoring in acute promyelocytic leukemia.0
    315557232019Educational Case: Acute Promyelocytic Leukemia With PML-RARA.0
    314470652019Characterization of a rarely reported STAT5B/RARA gene fusion in a young adult with newly diagnosed acute promyelocytic leukemia with resistance to ATRA therapy.3
    315791352019A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms.1
    310287442019Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders.12
    308061062019Myeloid neoplasm with eosinophilia and PCM1-JAK2 associated with acute promyelocytic leukemia with PML-RARA.1
    314475642019A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion; and literature review.7
    314314732019A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells.4
    313962782019HDAC and HMT Inhibitors in Combination with Conventional Therapy: A Novel Treatment Option for Acute Promyelocytic Leukemia.3
    313719842019t(15; 17) associated with primary myelofibrosis: a case report of an unusual clinical presentation and diagnostic dilemma.1
    308099812019The Incidence and Immunophenotypic and Genetic Features of JL1 Expressing Cells and the Therapeutic Potential of an Anti-JL1 Antibody in De Novo Pediatric Acute Leukemias.1

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    Summary

    Note

    FAB criteria AML M3
  • at least 20% of bone marrow cells are abnormal promyelocytes, with a characteristic pattern of heavy granulation
  • characteristic cells contain bundles of Auer rods ("faggots")

    FAB criteria AML M3v

  • As other AML, at least 20% of bone marrow cells are blast cells. Blast cells have minimal granulation, relative scarcity of cells with heavy granulation and cells containing multiple Auer rods. The nucleus of blast cells is bilobed, multilobed or reniform, but the majority of cells are either devoid of granules or contain only a few fine azurophil granules. However, at least a few cells with all the cytoplasmic features of typical AML M3 are present. If these are overlooked, the cases are likely misdiagnosed as monocytic leukemia. The M3v morphology is mainly a feature of the peripheral blood cells ­ bone marrow morphology is closer to that of typical AML M3.
  • both subtypes show a very strong myeloperoxidase reaction and a negative reaction for non-specific esterase. Exceptional APL PML/RARA cases with basophilic granulations, metachromatic with toluidine blue, can be MPO negative (Invernizzi R et al , 1995).

    Immunophenotype

  • mature myeloid phenotype, characteristic but not diagnostic:
  • CD34 negative, HLA-DR negative, CD33 positive, CD13 positive.
  • Aberrant expression of CD56 is observed in approximately 10% of APL patients and is associated with a higher WBC count, a more frequent bcr3 isoform and, in some series of patients, a shorter event free survival (Testa and Lo-Coco, 2016).
  • in M3 but not M3v: characteristic light scatter pattern, strong unspecific fluorescence signal

    WHO classification (2008, updated 2016)

  • APL with t(15;17)(q24;q21) PML/ RARA (WHO 2008) is now reported as APL with PML/RARA (WHO 2016)
  • Other very rare AML M3/M3v harbouring recurring translocations involving RARA with variant genes other than PML previously mentioned as AML with variant partners of RARA (WHO 2008) should be reported accordingly:
  • AML with t(11;17)(q23;q21) ZBTB16/RARA (previously named PLZF/RARA),
  • AML with t(11;17)(q13;q21) NUMA1/RARA,
  • AML with t(5;17)(q35;q21) NPM1/RARA,
  • AML with der(17); STAT5B/RARA (either cryptic abnormality leading to normal chromosome 17 on karyotype or abnormal der(17) both due to complex rearrangements involving STAT5B located downstream to RARA on band 17q21.2 and oriented 5-3 telomere to centromere ).
  • Citation

    Marina Lafage ; Marina Lafage

    M3/M3v acute myeloid leukemia (AML M3/M3v)
    Acute promyelocytic leukemia (APL)
    Acute promyelocytic leukemia (APL) PML/RARA

    Atlas Genet Cytogenet Oncol Haematol. 2017-04-01

    Online version: http://atlasgeneticsoncology.org/haematological/1240/m3anllid1240

    Historical Card

    2006-01-01 M3/M3v acute myeloid leukemia (AML M3/M3v)
    Acute promyelocytic leukemia (APL)
    Acute promyelocytic leukemia (APL) PML/RARA
     by  Claudia Schoch 

    MLL Münchner Leukümielabor GmbH, Max-Lebsche-Platz 31, 81377 München, Germany

    External Links