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
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

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