t(3;8)(q26.2;q24) Often Leads to MECOM/MYC Rearrangement and Is Commonly Associated with Therapy-Related Myeloid Neoplasms and/or Disease Progression
2018; Elsevier BV; Volume: 21; Issue: 2 Linguagem: Inglês
10.1016/j.jmoldx.2018.10.005
ISSN1943-7811
AutoresGuilin Tang, Shimin Hu, Sa A. Wang, Wei Xie, Pei Lin, Jie Xu, Gökçe Törüner, Ming Zhao, Jun Gu, Madison Doty, Shaoying Li, L. Jeffrey Medeiros, Zhenya Tang,
Tópico(s)Chronic Myeloid Leukemia Treatments
Resumot(3;8)(q26.2;q24) is a rare recurrent cytogenetic abnormality that is associated with myeloid neoplasms. Of 20 patients with t(3;8)(q26.2,q24), 8 had therapy-related acute myeloid leukemia (AML), 3 therapy-related myelodysplastic syndrome, 4 blast phase of chronic myeloid leukemia, 1 relapsed AML, 1 AML transformed from chronic myelomonocytic leukemia, 1 blast phase of an unclassifiable myeloproliferative neoplasm, 1 de novo myelodysplastic syndrome, and 1 de novo AML. Nineteen patients presented with cytopenia. Multilineage dysplasia was observed in 16/18 patients, and megakaryocytes were markedly decreased in 11/20 patients. Blasts showed a primitive myeloid immunophenotype in 17 patients, negative for myeloperoxidasein in 14/17, and aberrant CD7 expression in 5/17 patients. Fluorescence in situ hybridization showed MECOM rearrangement in 18/19 and MYC in 16/18 patients. Myc was shown to be expressed in all 14 cases assessed. Gene mutation testing was performed in 14 patients, and 7 showed at least one mutation including ASXL1 (2/6), TET2 (2/6), SRSF2 (2/6), and NRAS (2/13). At last clinical follow-up, 18 patients died and 2 were alive with persistent disease, with a median survival of 6 months. The authors conclude that t(3;8)(q26.2;q24) often leads to MECOM and MYC rearrangement, occurs predominantly in therapy-related myeloid neoplasms or at disease progression, and shares some similarities with myeloid neoplasms associated with inv(3)/GATA2-MECOM. Patients with myeloid neoplasms associated with t(3;8)(q26.2;q24) have a dismal outcome. t(3;8)(q26.2;q24) is a rare recurrent cytogenetic abnormality that is associated with myeloid neoplasms. Of 20 patients with t(3;8)(q26.2,q24), 8 had therapy-related acute myeloid leukemia (AML), 3 therapy-related myelodysplastic syndrome, 4 blast phase of chronic myeloid leukemia, 1 relapsed AML, 1 AML transformed from chronic myelomonocytic leukemia, 1 blast phase of an unclassifiable myeloproliferative neoplasm, 1 de novo myelodysplastic syndrome, and 1 de novo AML. Nineteen patients presented with cytopenia. Multilineage dysplasia was observed in 16/18 patients, and megakaryocytes were markedly decreased in 11/20 patients. Blasts showed a primitive myeloid immunophenotype in 17 patients, negative for myeloperoxidasein in 14/17, and aberrant CD7 expression in 5/17 patients. Fluorescence in situ hybridization showed MECOM rearrangement in 18/19 and MYC in 16/18 patients. Myc was shown to be expressed in all 14 cases assessed. Gene mutation testing was performed in 14 patients, and 7 showed at least one mutation including ASXL1 (2/6), TET2 (2/6), SRSF2 (2/6), and NRAS (2/13). At last clinical follow-up, 18 patients died and 2 were alive with persistent disease, with a median survival of 6 months. The authors conclude that t(3;8)(q26.2;q24) often leads to MECOM and MYC rearrangement, occurs predominantly in therapy-related myeloid neoplasms or at disease progression, and shares some similarities with myeloid neoplasms associated with inv(3)/GATA2-MECOM. Patients with myeloid neoplasms associated with t(3;8)(q26.2;q24) have a dismal outcome. MECOM (MDS1 and EVI1 complex locus), located at chromosome 3q26.2, consists of two genes, MDS1 and EVI1, with MDS1 located 5′ of EVI1. This complex produces two mRNA products: EVI1 and MDS1-EVI1 fusion. Patients with 3q26.2 abnormalities often show high levels of EVI1 and MDS1-EVI1 expression, but only increased EVI1expression has been associated with shorter overall survival and shorter event-free survival.1Barjesteh van Waalwijk van Doorn-Khosrovani S. Erpelinck C. van Putten W.L. 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Douet-Guilbert N. 3q26/EVI1 rearrangements in myeloid hemopathies: a cytogenetic review.Future Oncol. 2015; 11: 1675-1686Crossref PubMed Scopus (25) Google Scholar EVI1 expression is low or negative in normal bone marrow, but is high in blasts of virtually all adult acute myeloid leukemia (AML) with inv(3) or t(3;3)(q21;q26.2), and 6% to 11% of AML without 3q26.2 abnormalities, particularly those associated with monosomy 7 (−7) or a KMT2A (MLL) rearrangement.1Barjesteh van Waalwijk van Doorn-Khosrovani S. Erpelinck C. van Putten W.L. Valk P.J. van der Poel-van de Luytgaarde S. Hack R. Slater R. Smit E.M. Beverloo H.B. Verhoef G. Verdonck L.F. Ossenkoppele G.J. Sonneveld P. de Greef G.E. Lowenberg B. Delwel R. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients.Blood. 2003; 101: 837-845Crossref PubMed Scopus (296) Google Scholar, 8Lugthart S. Groschel S. Beverloo H.B. Kayser S. Valk P.J. van Zelderen-Bhola S.L. Ossenkoppele G.J. 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To date, a total of 19 cases have been reported in the literature (including 6 cases from the authors' institution).17Lin P. Medeiros L.J. Yin C.C. Abruzzo L.V. Translocation (3;8)(q26;q24): a recurrent chromosomal abnormality in myelodysplastic syndrome and acute myeloid leukemia.Cancer Genet Cytogenet. 2006; 166: 82-85Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Lin P. Lennon P.A. Yin C.C. Abruzzo L.V. Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24).Cancer Genet Cytogenet. 2009; 193: 119-122Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 19Xu X. Su M. Levy N.B. Mohtashamian A. Monaghan S. Kaur P. Zaremba C. Garcia R. Broome H.E. Dell'Aquila M.L. Wang H.Y. Myeloid neoplasm with t(3;8)(q26;q24): report of six cases and review of the literature.Leuk Lymphoma. 2014; 55: 2532-2537Crossref PubMed Scopus (5) Google Scholar, 20Kubota Y. Ichinohe T. Yoshimura M. Itamura H. Hisatomi T. Fukushima N. Sueoka E. Kimura S. 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Wei P. Kanagal-Shamanna R. Yin C.C. Zuo Z. Routbort M.J. Tang G. Tang Z. Jorgensen J.L. Luthra R. Ravandi F. Kantarjian H.M. DiNardo C.D. Medeiros L.J. Wang S.A. Patel K.P. Persistent IDH1/2 mutation in remission can predict relapse in patients with acute myeloid leukemia.Haematologica. 2019; 104: 305-311Crossref PubMed Scopus (44) Google Scholar, 25Isoda A. Sakurai A. Ogawa Y. Miyazawa Y. Saito A. Matsumoto M. Sawamura M. Chronic inflammatory demyelinating polyneuropathy accompanied by chronic myelomonocytic leukemia: possible pathogenesis of autoimmunity in myelodysplastic syndrome.Int J Hematol. 2009; 90: 239-242Crossref PubMed Scopus (15) Google Scholar Similar to t(3;3)/inv(3), t(3;8) is also mainly seen in AML, myelodysplastic syndrome (MDS), or blast phase of chronic myeloid leukemia (CML).17Lin P. Medeiros L.J. Yin C.C. Abruzzo L.V. Translocation (3;8)(q26;q24): a recurrent chromosomal abnormality in myelodysplastic syndrome and acute myeloid leukemia.Cancer Genet Cytogenet. 2006; 166: 82-85Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Lin P. Lennon P.A. Yin C.C. Abruzzo L.V. Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24).Cancer Genet Cytogenet. 2009; 193: 119-122Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 19Xu X. Su M. Levy N.B. Mohtashamian A. Monaghan S. Kaur P. Zaremba C. Garcia R. Broome H.E. Dell'Aquila M.L. Wang H.Y. Myeloid neoplasm with t(3;8)(q26;q24): report of six cases and review of the literature.Leuk Lymphoma. 2014; 55: 2532-2537Crossref PubMed Scopus (5) Google Scholar, 20Kubota Y. Ichinohe T. Yoshimura M. Itamura H. Hisatomi T. Fukushima N. Sueoka E. Kimura S. Acute myeloid leukemia with t(3;8)(q26;q24) complicated by diabetes insipidus.Ann Hematol. 2016; 95: 653-655Crossref PubMed Scopus (4) Google Scholar, 22Sato K. Sakai H. Uchida A. Uemura Y. Tsuruoka Y. Yokoi S. Nishio Y. Matsunawa M. Suzuki Y. Isobe Y. Kato M. Tomita N. Inoue Y. Miura I. Acute myeloid leukemia with t (3;8) (q26.2;q24), a simple variant of 3q26.2/EVI1 translocation.Rinsho Ketsueki. 2017; 58: 315-322PubMed Google Scholar, 23Mertens F. Johansson B. Billstrom R. Engquist L. Mitelman F. A case of myelodysplastic syndrome with high platelet counts and a t(3;8)(q26;q24).Cancer Genet Cytogenet. 1987; 27: 1-4Abstract Full Text PDF PubMed Scopus (19) Google Scholar Among the reported cases, EVI1 was shown to be involved in most cases, but it is not clear whether MYC is involved. In addition, the molecular mutation profile of this group of patients is largely unknown. In this study, the clinicopathologic, cytogenetic, and molecular features of 20 patients with myeloid neoplasms associated with t(3;8)(q26.2;q24) are reported. The cytogenetics database at The University of Texas MD Anderson Cancer Center was searched for cases with t(3;8)(q26;q24) from January 1, 1998, to May 30, 2018. Clinical data, pathologic findings, and the results of flow cytometric immunophenotyping, conventional cytogenetic analysis, fluorescence in situ hybridization (FISH), and gene mutation analysis were reviewed. All samples were collected following institutional guidelines with informed consent in accord with the Declaration of Helsinki. Wright-Giemsa–stained peripheral blood and bone marrow (BM) aspirate smears, and hematoxylin-eosin–stained BM core biopsy sections were reviewed. Myelofibrosis was evaluated by reticulin and trichrome stains performed on the BM core biopsy specimens on cases in which the biopsy specimen was available. The grade of myelofibrosis was based on the European Consensus on grading of BM fibrosis.26Thiele J. Kvasnicka H.M. Facchetti F. Franco V. van der Walt J. Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity.Haematologica. 2005; 90: 1128-1132PubMed Google Scholar Flow cytometric immmunophenotypic analysis was performed at the time t(3;8) was detected. Antibodies against the following antigens were used: CD2, CD3, CD4, CD5, CD7, CD9, CD10, CD11b, CD13, CD14, CD19, CD20, CD22, CD25, CD34, CD38, CD41, CD56, CD64, CD79b, CD117, CD123, HLA-DR, myeloperoxidase, and terminal deoxynucleotide transferase (BD Biosciences, San Jose, CA). Immunohistochemical analysis for Myc was performed on formalin-fixed, paraffin-embedded sections of the BM core biopsy or clot specimens using a pre-diluted rabbit monoclonal antibody specific for Myc (c-Myc, clone Y69; Ventana Medical Systems, Tucson, AZ) according to the manufacturer's instructions. Conventional G-banded chromosomal analysis was performed on unstimulated 24-hour and 48-hour BM aspirate cultures using standard techniques. Twenty metaphases were analyzed, and the results were reported using the 2016 International System for Human Cytogenetics Nomenclature (ISCN 2016). A complex karyotype was defined as ≥3 chromosomal abnormalities. FISH analysis was performed on BM culture cells or Wright-Giemsa–stained BM smears using dual-color break-apart probes for MECOM or MYC (Abbott Molecular, Des Plaines, IL) separately according to the manufacturer's instructions. Molecular analysis was performed on a subset of patients as a part of the routine clinical work-up. Next-generation sequencing for somatic mutations was performed in six patients with targeted 28-gene or 81-gene panel as described previously.24Ok C.Y. Loghavi S. Sui D. Wei P. Kanagal-Shamanna R. Yin C.C. Zuo Z. Routbort M.J. Tang G. Tang Z. Jorgensen J.L. Luthra R. Ravandi F. Kantarjian H.M. DiNardo C.D. Medeiros L.J. Wang S.A. Patel K.P. Persistent IDH1/2 mutation in remission can predict relapse in patients with acute myeloid leukemia.Haematologica. 2019; 104: 305-311Crossref PubMed Scopus (44) Google Scholar Overall survival was estimated by the Kaplan-Meier method from the date of t(3;8) detection until death from any cause (censored at last follow-up for alive patients). The study group included 12 men and 8 women, with a median age of 61 years (range, 21 to 79 years) at the time when t(3;8) was first detected. Six cases (#3, #4, #5, #15, #18, and #20) have been reported previously.17Lin P. Medeiros L.J. Yin C.C. Abruzzo L.V. Translocation (3;8)(q26;q24): a recurrent chromosomal abnormality in myelodysplastic syndrome and acute myeloid leukemia.Cancer Genet Cytogenet. 2006; 166: 82-85Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Lin P. Lennon P.A. Yin C.C. Abruzzo L.V. Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24).Cancer Genet Cytogenet. 2009; 193: 119-122Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Before the detection of t(3;8), 18 patients had a history of malignancy and received different treatments (Supplemental Table S1). Eleven patients (Cases #1 to #11) had a history of malignancy (solid tumor, lymphoma, or myeloma) and received cytotoxic therapies, including chemotherapies, radiation, and/or hematopoietic stem cell transplant or liver transplant; four patients (#12 to 15) had a history of CML and received interferon or tyrosine kinase inhibitors (TKI); Patient #16 had a history of myeloproliferative neoplasm, unclassifiable (MPN, NOS); Patient #17 had a history of chronic myelomonocytic leukemia (CMML) that later progressed to AML; and Patient #18 had a history of CMML. These three patients (Cases #16 to 18) received chemotherapies and hypomethylating agents. The interval from the diagnosis of primary malignancy to the detection of t(3;8) was 35 months (range, 9 to 65 months) for Cases #1 to #18. Patient #19 had a long history of Fanconi syndrome and received danazol and transfusion; Patient #20 had no significant history. The diagnosis and classification of these cases at the time of t(3;8) detection are summarized in Table 1. Eleven patients (Cases #1 to #11) had therapy-related myeloid neoplasms: three therapy-related MDS, and eight therapy-related AML; four (Cases #12 to #15) had blast phase of CML; two (Cases #16 and #18) had AML transformed from MPN or CMML; one (Case #17) had relapsed AML that had progressed from CMML; one (Case #19) had de novo MDS with excess blasts, and one (Case #20) had de novo AML (36% blasts) who also had untreated chronic lymphocytic leukemia (40% lymphocytes) in the BM (Table 1).Table 1Clinical Features, and Peripheral Blood and Bone Marrow FindingsCaseSex/age, yearsDiagnosisPeripheral blood findingsBone marrow findingsTreatments and follow-upWBC, ×109/LHgb, g/dLPlt, ×109/LBlast, %Cellular, %Blast, %DysplasiaMegasIHC MYC, %TreatmentSurvival, monthsOutcome1M/63t-MDS4.410.13604011MultilineageDecreased20Vidaza2AWD2M/40t-MDS1.687.70204MultilineageDecreased20Cytarabine7Dead3∗Cases reported previously.17,18M/56t-MDS1.48.1100107MultilineageDecreasedNA5-Azacitidine10Dead4∗Cases reported previously.17,18F/48t-AML8.51013368072MultilineageDecreasedNACytarabine10Dead5∗Cases reported previously.17,18F/68t-AML4.211.719701025MultilineageNormalNAMultiple20Dead6F/58t-AML2.210.326318030MultilineageDecreased70Multiple14Dead7F/65t-AML3.38.3119798061MultilineageIncreased50NA1Dead8F/75t-AML10.610.129285550MultilineageDecreased40Multiple6AWD9F/60t-AML1.466203046MultilineageDecreased30CIA, decitabine2Dead10M/66t-AML1.581494018MultilineageNormal20No1Dead11F/53t-AML7.71068904090NAIncreased60Multiple5Dead12M/64CML, BP813.1177659044MultilineageDecreased50Decitabine4Dead13M/62CML, BP35.412.850828557MultilineageDecreased70NA11Dead14M/53CML, BP78.49.053310020NoDecreasedNAChemo, TKI6Dead15∗Cases reported previously.17,18F/47CML, BP1.210.69503050MultilineageNormal20NA1Dead16M/72MPN, BP5.39.52409013NoNormal30Clofarabine, cytarabine4Dead17M/59AML, relapse47.19.3124459550MultilineageIncreased30Multiple3Dead18∗Cases reported previously.17,18M/73AML, M517.310.31759071NADecreasedNANA4Dead19M/21MDS-EB2.66.61462457MultilineageNormal20Decitabine, SCT8Dead20∗Cases reported previously.17,18M/79AML, CLL139.551138036MultilineageIncreasedNANA6DeadF, female; M, male; AML, acute myeloid leukemia; AMML, acute myelomonocytic leukemia; AWD, alive with disease; BP, blast phase; Chemo, chemotherapy; CIA, clofarabine, idarubicin, and cytarabine; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; Hgb, hemoglobin; IHC, immunohistochemistry; MDS-EB, myelodysplastic syndrome with excess blasts; Megas*, number of megakaryocytes; MPN, myeloproliferative neoplasm; NA, not available; Plt, platelets; SCT, stem cell transplant; t-, therapy-related; TKI, tyrosine kinase inhibitors; WBC, white blood cell count.∗ Cases reported previously.17Lin P. Medeiros L.J. Yin C.C. Abruzzo L.V. Translocation (3;8)(q26;q24): a recurrent chromosomal abnormality in myelodysplastic syndrome and acute myeloid leukemia.Cancer Genet Cytogenet. 2006; 166: 82-85Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 18Lin P. Lennon P.A. Yin C.C. Abruzzo L.V. Chronic myeloid leukemia in blast phase associated with t(3;8)(q26;q24).Cancer Genet Cytogenet. 2009; 193: 119-122Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Open table in a new tab F, female; M, male; AML, acute myeloid leukemia; AMML, acute myelomonocytic leukemia; AWD, alive with disease; BP, blast phase; Chemo, chemotherapy; CIA, clofarabine, idarubicin, and cytarabine; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; Hgb, hemoglobin; IHC, immunohistochemistry; MDS-EB, myelodysplastic syndrome with excess blasts; Megas*, number of megakaryocytes; MPN, myeloproliferative neoplasm; NA, not available; Plt, platelets; SCT, stem cell transplant; t-, therapy-related; TKI, tyrosine kinase inhibitors; WBC, white blood cell count. Treatment information after the detection of t(3;8)(q26.2;q24) are summarized in Table 1. Fourteen patients received chemotherapy and/or hypomethylating agents, one patient (Case #14) also received TKI, and one (Case #19) underwent cord blood stem cell transplant. Unfortunately, none of the patients achieved remission. At the last follow-up, 18 patients died and 2 were alive but with persistent disease. The median overall survival was 6 months (Figure 1A). Patient survival was compared between patients with t(3;8) as a sole abnormality or plus one additional abnormality other than −7 (n = 9) versus patients with −7 and/or complex karyotype (n = 11). There was no difference in overall survival between these two patient groups (Figure 1B). The survival of the 20 patients in this cohort was also compared with matched group of 44 patients with therapy-related AML/MDS without t(3;8), the overall survival was significantly inferior in patients with t(3;8) versus the matched group (6 versus 10.4 months; P = 0.0213) (Figure 1C). Blood counts and BM findings at the time of t(3;8) detection are summarized in Table 1. Nineteen patients had cytopenias: 7 pancytopenia, 18 anemia (median hemoglobin level, 9.7 g/dL), and 16 thrombocytopenia (median platelet counts, 51.5 × 109/L). The number of megakaryocytes was markedly decreased in 11 patients (Figure 2A), normal in 5 patients, and increased in 4 patients (Figure 2D). Multilineage dysplasia was observed in 16/18 patients who had adequate megakaryocytes and maturing granulocytes/erythroblasts to evaluate (Figure 2, B and E). Megakaryocytes were small, hypolobated, and dysplastic (Figure 2D). A total of 10 patients were evaluated for myelofibrosis: 5 normal, 4 mild (MF-1), and 1 marked (MF-3). Eighteen patients (except Cases #1 and #12) had flow cytometric immunophenotyping performed, 17 had a myeloid (CD13+/CD33+/CD117+) and 1 (Case #18) had a monocytic (CD14+/CD64+) immunophenotype. Myeloperoxidase was negative in myeloblasts in 13/17 cases assessed; CD7 was expressed in 5/17 and CD19 in 2/17 cases. Evaluation of Myc expression by immunohistochemistry was performed in 14 patients who had BM material (core or clot) available. All cases showed variable expression of Myc, ranging from about 20% to 70% positive cells. Expression of Myc correlated loosely with the percentage of blasts in BM (Figure 2, C and F, and Table 1). Fourteen patients had a karyotype available before the detection of t(3;8): six (Cases #1, #3, #5, #6, #16, and #17) had a normal karyotype; four (Cases #12 to #15) had t(9;22)/BCR-ABL1; one (Case #19) had del(7q); two (Cases #4 and #9) had therapy-related MDS/AML with −7; and one (Case #7) had a complex karyotype with t(11;14)/CCND1-IGH (Supplemental Table S1). The karyotypes when t(3;8) was detected are summarized in Table 2: 19 patients had t(3;8)(q26.2;q24), and 1 (Case #14) had ins(8;3)(q24.2;q26.2q26.2). Four patients had t(3;8) as a sole abnormality, seven had one additional chromosomal abnormality, and nine patients had two or more additional chromosomal abnormalities (complex karyotype). All cases had t(3;8) or ins(8;3) in the stemline (Figure 3A). Monosomy 7 was the most common additional abnormality, detected in five patients.Table 2Cytogenetic and Molecular Findings upon t(3;8) DetectionCaseKaryotypeFISH MECOMFISH MYCMolecular mutationPositiveNegative146,XY,t(3;8)(q26.2;q24.2)[16]/46,XY[4]PositivePositiveGATA2All others245,XY,t(3;8)(q26.2;q24.2),-7[19]/46,XY[1]PositivePositiveNoc-Kit, FLT3, RAS3†Cases reported previously.17,1845,XY,t(3;8)(q26;q24.2),-7[14]PositivePositiveNANA4†Cases reported previously.17,1846,XX,t(3;8)(q26.2;q24.2),-7,*mar[
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