| Written | 1998-04 | Jean-Loup Huret, Christine Chomienne |
| | Laboratoire de Biologie Cellulaire Hématopoïétique, EP-107 CNRS, Institut d'Hématologie, Hôpital Saint Louis, Centre Hayem, Paris, France |
| Updated | 2016-03 | Pino J. Poddighe, Daniel Olde Weghuis |
| | 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 |
| ICD-Topo |
C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS |
| ICD-Morpho |
9866/3 Acute promyelocytic leukaemia with t(15;17)(q22;q12); PML-RARA
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| ICD-Morpho |
9920/3 Therapy-related myeloid neoplasms
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| Atlas_Id |
1035 |
| 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. |
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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. |
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| 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 / cell stem 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. |
| 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). |
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| 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. |
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| 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. |
| Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. |
| Alcalay M, Zangrilli D, Pandolfi PP, Longo L, Mencarelli A, Giacomucci A, Rocchi M, Biondi A, Rambaldi A, Lo Coco F |
| Proceedings of the National Academy of Sciences of the United States of America. 1991 ; 88 (5) : 1977-1981. |
| PMID 1848017 |
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| Cytogenetic studies in acute promyelocytic leukemia: a survey of secondary chromosomal abnormalities. |
| Berger R, Le Coniat M, Derré J, Vecchione D, Jonveaux P |
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| PMID 1797083 |
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| Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. |
| Borrow J, Goddard AD, Sheer D, Solomon E |
| Science (New York, N.Y.). 1990 ; 249 (4976) : 1577-1580. |
| PMID 2218500 |
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| Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy: The European experience. European APL Group. |
| Fenaux P, Chastang C, Chomienne C, Castaigne S, Sanz M, Link H, Löwenberg B, Fey M, Archim-Baud E, Degos L |
| Leukemia & lymphoma. 1995 ; 16 (5-6) : 431-437. |
| PMID 7787753 |
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| Treatment of acute promyelocytic leukemia by retinoids. |
| Fenaux P, Wang ZZ, Degos L. |
| Curr Top Microbiol Immunol 2007; 313:101-128. |
| PMID 17217041 |
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| Genomic 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, Alcalay M, Fagioli M, Zangrilli D, Mencarelli A, Diverio D, Biondi A, Lo Coco F, Rambaldi A, Grignani F |
| The EMBO journal. 1992 ; 11 (4) : 1397-1407. |
| PMID 1314166 |
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| Acute promyelocytic leukemia. |
| Warrell RP Jr, de Thé H, Wang ZY, Degos L |
| The New England journal of medicine. 1993 ; 329 (3) : 177-189. |
| PMID 8515790 |
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| The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. |
| de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A |
| Nature. 1990 ; 347 (6293) : 558-561. |
| PMID 2170850 |
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