Diagnosis of Variant Translocations in Acute Promyelocytic Leukemia

Published:August 31, 2021DOI:https://doi.org/10.1016/j.yamp.2021.06.002
      Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia that is associated with the development of disseminated intravascular coagulopathy, which poses a medical emergency.

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      References

        • Arber D.
        • Brunning R.
        • Le Beau M.
        • et al.
        WHO classification of tumours of haematopoietic and lymphoid tissues (Revised 4th Edition).
        IRAC, Lyon2017
        • Adams J.
        • Nassiri M.
        Acute promyelocytic leukemia: a review and discussion of variant translocations.
        Arch Pathol Lab Med. 2015; 139: 1308-1313
        • Toh C.H.
        • Alhamdi Y.
        • Abrams S.T.
        Current pathologic and laboratory considerations in the diagnosis of disseminated intravascular coagulation.
        Ann Intern Med. 2016; 36: 505-512
        • Bennett J.
        • Catovsky D.
        • Daniel M.
        • et al.
        Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group.
        Ann Intern Med. 1985; 103: 620-625
        • Bennett J.
        • Catovsky D.
        • Daniel M.
        • et al.
        Proposals for the classification of acute leukaemias. French-American-British (FAB) cooperative group.
        Br J Haematol. 1976; 33: 1365-2141
        • George T.
        • Wilson C.S.
        Promyelocytes.
        in: Color atlas of hematology: an illustrated field guide based on proficiency testing. 2nd edition. CAP, Northfield, Illinois2018: p170-p171
        • Foucar K.
        • Reichard K.
        • Czuchlewski D.
        Acute myeloid leukemia.
        in: 4th edition. Bone marrow pathology. vol. 1. ASCP, Chicago2020: 397-443
        • Gorczyca W.
        Acute myeloid leukemia with recurrent genetic changes.
        in: Flow cytometry in neoplastic hematology. 3rd ed. CRC Press, Boca Raton, Florida2017: 392-398
        • Lin P.
        • Hao S.
        • Medeiros L.J.
        • et al.
        Expression of CD2 in acute promyelocytic leukemia correlates with short form of PML-RARA transcripts and poorer prognosis.
        Am J Clin Pathol. 2004; 121: 402-407
        • Foley R.
        • Soamboonsrup P.
        • Carter R.F.
        • et al.
        CD34-positive acute promyelocytic leukemia is associated with leukocytosis, microgranular/hypogranular morphology, expression of CD2 and bcr3 isoform.
        Am J Hematol. 2001; 67: 34-41
        • Ono T.
        • Takeshita A.
        • Kishimoto Y.
        • et al.
        Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts.
        Cancer Sci. 2014; 105: 97-104
        • Sainty D.
        • Liso V.
        • Cantù-Rajnoldi A.
        • et al.
        A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements.
        Blood. 2000; 96: 1287-1296
        • Geoffroy M.-C.
        • de Thé H.
        Classic and variants APLs, as viewed from a therapy response.
        Cancers. 2020; 12: 967
        • Choppa P.C.
        • Gomez J.
        • Vall H.G.
        • et al.
        A novel method for the detection, quantitation, and breakpoint cluster region determination of t(15;17) fusion transcripts using a one-step real-time multiplex RT-PCR.
        Am J Clin Pathol. 2001; 119: 137-144
        • Jiang X.
        • Chen S.
        • Zhu X.
        • et al.
        Development and validation of a droplet digital PCR assay for the evaluation of PML-RARα fusion transcripts in acute promyelocytic leukemia.
        Mol Cell Probes. 2020; 53: 101617
        • Kim M.J.
        • Cho S.Y.
        • Kim M.H.
        • et al.
        FISH-negative cryptic PML-RARA rearrangement detected by long-distance polymerase chain reaction and sequencing analyses: a case study and review of the literature.
        Cancer Genet Cytogenet. 2010; 203: 278-283
        • Koshy J.
        • Qian Y.W.
        • Bhagwath G.
        • et al.
        Microarray, gene sequencing, and reverse transcriptase-polymerase chain reaction analyses of a cryptic PML-RARA translocation.
        Cancer Genet. 2012; 2015: 537-540
        • Mannan A.
        • Muhsen I.B.
        • Barragan E.
        • et al.
        Genotypic and phenotypic characteristics of acute promyelocytic leukemia translocation variants.
        Hematol Oncol Stem Cell Ther. 2020; 13: 189-201
        • Singh M.K.
        • Parihar M.
        • Arora N.
        • et al.
        Diagnosis of variant RARA translocation using standard dual-color dual-fusion PML/RARA FISH probes: An illustrative report.
        Hematol Oncol Stem Cell Ther. 2019; 12: 50-53
        • Zhang Y.
        • Frohman M.A.
        Using rapid amplification of cDNA ends (RACE) to obtain full-length cDNAs.
        Methods Mol Biol. 1997; 69: 61-87
        • Menezes J.
        • Acquadro F.
        • Perez-Pons de la Villa C.
        • et al.
        FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia.
        Haematologica. 2011; 96: 1565-1566
        • Stark R.
        • Grzelak M.
        • Hadfield J.
        RNA sequencing: the teenage years.
        Nat Rev Genet. 2019; 20: 631-656
        • Kukurba K.R.
        • Montgomery S.B.
        RNA sequencing and analysis.
        Cold Spring Harb Protoc. 2015; 2015: 951-969
        • Heyer E.E.
        • Deveson I.W.
        • Wooi D.
        • et al.
        Diagnosis of fusion genes using targeted RNA sequencing.
        Nat Commun. 2019; 10: 1388
        • Piskol R.
        • Ramaswami G.
        • Li J.B.
        Reliable identification of genomic variants from RNA-Seq data.
        Am J Hum Genet. 2013; 93: 641-651
        • Langabeer S.E.
        • Preston L.
        • Kelly J.
        • et al.
        Molecular profiling: a case of ZBTB16-RARA acute promyelocytic leukemia.
        Case Rep Hematol. 2017; 2017: 7657393
        • Jin Y.
        • Nenseth H.Z.
        • Saatcioglu F.
        Role of PLZF as a tumor suppressor in prostate cancer.
        Oncotarget. 2017; 8: 71317-71324
        • Lechevalier N.
        • Dulucq S.
        • Bidet A.
        A case of acute promyelocytic leukemia with unusual cytological features and a ZBTB16-RARA fusion gene.
        Br J Haematol. 2016; 174: 502
        • Wells R.A.
        • Hummel J.L.
        • De Koven A.
        • et al.
        A new variant translocation in acute promyelocytic leukemia: molecular characterization and clinical correlation.
        Leukemia. 1996; 10: 735-740
        • Sanz M.A.
        • Fenaux P.
        • Tallman M.S.
        • et al.
        Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European Leukemia Net.
        Blood. 2019; 133: 1630-1643
        • Rabade N.
        • Raval G.
        • Chaudhary S.
        • et al.
        Molecular heterogeneity in acute promyelocytic leukemia-A single center experience form India.
        Mediterr J Hematol Infect Dis. 2018; 10: e2018002
        • Liu Y.
        • Xu F.
        • Hu H.
        • et al.
        A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion and literature review.
        Oncotargets Ther. 2019; 12: 6157-6163
        • Alotaibi A.S.
        • Abdulrazzaq M.
        • Patel K.P.
        • et al.
        Acute promyelocytic leukemia (APL) with an IRF2BP2-RARA fusion transcript: an aggressive APL variant.
        Leuk Lymphoma. 2020; 61: 3018-3020
        • Carneiro F.R.G.
        • Ramalho-Oliveira R.
        • Mognol G.P.
        • et al.
        Interferon Regulatory Factor 2 Binding Protein 2 is a new NFAT1 partner and represses its transcriptional activity.
        Mol Cell Biol. 2011; 31: 2889-2901
        • Jovanovic J.V.
        • Chillon M.C.
        • Vincent-Fabert C.V.
        • et al.
        The cryptic IRF2BP2-RARA fusion transforms hematopoietic stem/progenitor cells and induces retinoid-sensitive acute promyelocytic leukemia.
        Leukemia. 2017; 31: 747-751
        • Mazharuddin S.
        • Chattopadhyay A.
        • Levy M.Y.
        • et al.
        IRF2BP2-RARA t(15;17)(q42.3;q21.2) APL blasts differentiate in response to all-trans retinoic acid.
        Leuk Lymphoma. 2018; 59: 2246-2249
        • Yan W.
        • Zhang G.
        Molecular characteristics and clinical significance of 12 fusion genes in acute promyelocytic leukemia: a systematic review.
        Acta Haematol. 2016; 136: 1-15
        • Shimomura Y.
        • Mitsuii H.
        • Yamashita Y.
        • et al.
        New variant of acute promyelocytic leukemia with IRF2BP2-RARA fusion.
        Cancer Sci. 2016; 107: 1165-1168
        • Sobas M.
        • Talarn-Forcadell M.C.
        • Martinez-Cuadron D.
        • et al.
        PLZF-RARα, NPM1-RARα, and other acute promyelocytic leukemia variants: the PETHEMA registry experience and systematic literature review.
        Cancers. 2020; 21: 1313
        • Nicci C.
        • Ottaviani E.
        • Luatti S.
        • et al.
        Molecular and cytogenetic characterization of a new case of t(5;17)(q35;q21) variant acute promyelocytic leukemia.
        Leukemia. 2005; 19: 470-472
        • Mannan A.
        • Muhsen I.N.
        • Barragán E.
        • et al.
        Genotypic and phenotypic characteristics of acute promyelocytic leukemia translocation variants.
        Hematol Oncol Stem Cell Ther. 2020; 13: 189-201
        • Zhang C.
        • Wang Y.
        • Liu B.
        • et al.
        Clinical characteristics of acute promyelocytic leukemia with the STAT5B-RARA fusion gene.
        Blood Cells Mol Dis. 2018; 69: 71-73
        • Peterson J.F.
        • He R.R.
        • Nayer H.
        • et al.
        Characterization of a rarely reported STAT5B/RARA gene fusion in a young adult with newly diagnosed acute promyelocytic leukemia with resistance to ATRA therapy.
        Cancer Genet. 2019; 237: 51-54
        • Kang J.H.
        • Lee S.H.
        • Lee J.
        • et al.
        The mutation of BCOR is highly recurrent and oncogenic in mature T-cell lymphoma.
        BMC Cancer. 2021; 21: 1
        • Yamamoto Y.
        • Tsuzuki S.
        • Tsuzuki M.
        • et al.
        BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia.
        Blood. 2010; 116: 4274-4283
        • Ichikawa S.
        • Takahashi T.
        • Fujiwara T.
        • et al.
        Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene.
        Cancer Genet. 2015; 208: 162-163
        • Iwasaki J.
        • Kondo T.
        • Darmanin S.
        • et al.
        FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.
        Ann Hematol. 2014; 93: 1473-1481
        • Kondo T.
        • Mori A.
        • Darmanin S.
        • et al.
        The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia.
        Haematologica. 2008; 93: 1414-1416
        • Nakanishi T.
        • Nakaya A.
        • Nishio Y.
        • et al.
        A variant acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms.
        Hematol Rep. 2019; 11: 49-51
        • Cheng C.K.
        • Wang A.Z.
        • Wong T.H.Y.
        • et al.
        FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia.
        Blood. 2017; 129: 2705-2709
        • Li J.
        • Zhong H.-Y.
        • Zhang Y.
        • et al.
        GTF2I-RARA is a novel fusion transcript in a t(7;17) variant of acute promyelocytic leukaemia with clinical resistance to retinoic acid.
        Br J Haematol. 2015; 168: 904-908
        • Won D.
        • Shin S.Y.
        • Park C.J.
        • et al.
        OBFC2A/RARA: A novel fusion gene in variant acute promyelocytic leukemia.
        Blood. 2013; 121: 1432-1435
        • Wells R.A.
        • Catzavelos C.
        • Kamel-Reid S.
        Fusion of retinoic acid receptor a to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia.
        Nat Genet. 1997; 17: 109-113
        • Catalano A.
        • Dawson M.A.
        • Somana K.
        • et al.
        The PRKAR1A gene is fused to RARA in a new variant. Acute promyelocytic leukemia.
        Blood. 2007; 110: 4073-4076
        • Yao L.
        • Wen L.
        • Wang N.
        • et al.
        Identification of novel recurrent STAT3-RARA fusion in acute promyelocytic leukemia lacking t(15;17)(q22;q12)/PML-RARA.
        Blood. 2018; 131: 935-939
        • Osumi T.
        • Watanabe A.
        • Okamura K.
        • et al.
        Acute promyelocytic leukemia with a cryptic insertion of RARA into Tbl1xr1.
        Genes Chromosomes Cancer. 2019; 58: 820-823
        • Chen Y.
        • Shouyun L.
        • Zhou C.
        • et al.
        TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia.
        Blood. 2014; 124: 936-945
        • Chong M.-L.
        • Cheng H.
        • Xu P.
        • et al.
        TFG-RARA: a novel fusion gene in acute promyelocytic leukemia that is responsive to all-trans retinoic acid.
        Leuk Res. 2018; 74: 51-54
        • Fasan A.
        • Haferlach C.
        • Perglerovà K.
        • et al.
        Molecular landscape of acute promyelocytic leukemia at diagnosis and relapse.
        Haematologica. 2017; 102: e222-e224
        • Beitinjaneh A.
        • Jang S.
        • Roukoz H.
        • et al.
        Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review.
        Leuk Res. 2010; 34: 831-836
        • Testa U.
        • Lo-Coco F.
        Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients.
        Ann Hematol. 2016; 95: 673-680
        • Iaccarino L.
        • Ottone T.
        • Alfonso V.
        • et al.
        Mutational landscape of patients with acute promyelocytic leukemia at diagnosis and relapse.
        Am J Hematol. 2019; 94: 1091-1097
        • Yedla R.P.
        • Bala S.C.
        • Pydi V.R.
        • et al.
        Outcomes in adult acute promyelocytic leukemia: a decade experience.
        Clin Lymphoma Myeloma Leuk. 2020; 20: e158-e164
      1. Sanz MA, Coco FL, Martin G, et al. Retinoic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence. Haematologica 2005;1231-5.

        • Lo-Coco F.
        • Avvisati G.
        • Vignetti M.
        • et al.
        Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
        N Engl J Med. 2013; 369: 111-121
        • Sanz M.A.
        • Coco F.L.
        • Martin G.
        • et al.
        Definition of relapse risk and role of non-anthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups: Presented in part at the 41st meeting of the American Society of Hematology, New Orleans, LA, 1999.
        Blood. 2000; 96: 1247-1253
        • Jin B.
        • Zhang Y.
        • Hou W.
        • et al.
        Comparative analysis of causes and predictors of early death in elderly and young patients with acute promyelocytic leukemia treated with arsenic trioxide.
        J Cancer Res Clin Oncol. 2020; 146: 485-492