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#author("2025-07-07T20:13:43+09:00","","") #author("2025-07-07T20:14:28+09:00","","") [[AML with defining genetic abnormalities]] *Acute myeloid leukaemia with MECOM rearrangement [#u8b41cc1] #ref(chromosome3-MECOM loci.jpg,around,right,75%) ''MECOM – MDS1 and EVI1 complex locus'' = [[MECOM:https://www.ncbi.nlm.nih.gov/gene/?term=MECOM]] NCBIのページ Also known as: AML1-EVI-1, EVI1, KMT8E, MDS1, MDS1-EVI1, PRDM3, RUSAT2 昔からのヒトにはMECOMにコードされるEVI-1がかかわる融合タンパク質AML1-EVI-1がおなじみですねえ. ***3q26の異常 [#mf84e000] -染色体3q26上のEVI1(MECOM)の過剰発現につながる染色体再配列は,化学療法抵抗性で, %%%2年生存率10％未満%%%の予後不良な急性骨髄性白血病（AML）のサブタイプを規定する。 #br -正常な造血では,&color(#c9171e){''EVI1の発現は造血幹細胞(HSC)に限られ,自己複製する未分化な状態を維持するために必須である''};¬e{6:K Kataoka, T Sato, A Yoshimi, et al.Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity. J Exp Med, 208 (12) (2011), pp. 2403-2416};¬e{7:Y Zhang, S Stehling-sun, K Lezon-geyda, et al. PR-domain - containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function Blood, 118 (14) (2011), pp. 3853-3861}; #br -AMLでは,&color(#c9171e){''inv(3)(q21.3q26.2)やt(3;3)(q21.3;q26.2)などの染色体転座によって, 遠位のGATA2エンハンサーとEVI1プロモーターが並置され''};¬e{8:DA Arber, A Orazi, R Hasserjian, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood, 127 (20) (2016), pp. 2391-2405};¬e{9: H Yamazaki, M Suzuki, A Otsuki, et al. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell, 25 (4) (2014), pp. 415-427};¬e{10: S Groschel, MA Sanders, R Hoogenboezem, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in Leukemia. Cell, 157 (2) (2014), pp. 369-381};,%%%''MYB,C/EBPα,RUNX1''などの造血転写因子の動員によってEVI1の異常発現が引き起こされる%%%. #br -t(3;&color(#e60033){21};)(q26;&color(#e60033){q22};)などの転座はRUNX1-EVI1融合タンパク質の発現につながるが,t(3;&color(#e60033){8};)(q26;&color(#e60033){q24};)はMYCスーパーエンハンサーを乗っ取り,EVI1の発現異常を引き起こす¬e{13:S Ottema, R Mulet-Lazaro, C Erpelinck-Verschueren, et al. The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops. Nat Commun, 12 (5679) (2021), pp. 1-13}; #br -EVI1の過剰発現は,ある種のAMLサブタイプでは構造的再配列がない場合にも観察され,同様に予後不良と関連している¬e{14:M Russell, A List, P Greenberg, et al. Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Blood, 84 (4) (1994), pp. 1243-1248};¬e{15:S Groschel, RF Schlenk, J Engelmann, et al. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group. J Clin Oncol, 31 (1) (2013), pp. 95-103};¬e{16:V Stavropoulou, S Kaspar, L Brault, et al. MLL-AF9 expression in hematopoietic stem cells drives a highly invasive AML expressing EMT-related genes linked to poor outcome. Cancer Cell, 30 (1) (2016), pp. 43-58};. #br -EVI1の異常発現を引き起こす遺伝的事象や遺伝子制御機構は次第に明らかにされつつあるが,EVI1の分子機能や下流の標的はまだ十分に解明されていない。 #br -EVI1タンパク質は2つのジンクフィンガードメインを持ち,C末端結合タンパク質1/2（CTBP1/2）のような%%%corepressors%%%との 結合部位を持つ抑制ドメインによって隔てられている¬e{17:K Izutsu, M Kurokawa, Y Imai, et al.The corepressor CtBP interacts with Evi-1 to repress transforming growth factor β signaling Blood, 97 (9) (2001), pp. 2815-2822};¬e{18:J Turner, M Crossley Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators EMBO J, 17 (17) (1998), pp. 5129-5140};.しかし,適切な実験モデルがないため,EVI1が制御する転写プログラムの正確な構成や白血病発生に対する機能的な寄与は,ほとんど解明されていない。 #br ***Case presentation [#l622a7f5] 80歳代男性. 徐脈で治療中, 末梢血で血球異形成を指摘される. Hb8.8g/dl, RBC 402x10SUP{SIZE(8){4}}/μl, MCV 76, WBC 2500/μl, &color(#0000ff){''Plt. 3.9x10SUP{SIZE(8){4}}''}; #br #gallery(left,nowrap,noadd){{ > MECOM-HE01.jpg>BM clot-HE MECOM-HE02.jpg>BM clot-HE MECOM-ASDG-01.jpg>BM-ASD-Giemsa MECOM-ASDG-02.jpg>BM clot-ASD-Giemsa MECOM-ASDG-03.jpg>BM clot-ASD-Giemsa }} #gallery(left,nowrap,noadd){{ MECOM-ASDG-04.jpg>BM clot-ASD-Giemsa MECOM-ASDG-05.jpg>BM clot-ASD-Giemsa MECOM-CD34.jpg>CD34 MECOM-c-KIT-01.jpg>c-KIT }} #br #gallery(left,nowrap,noadd){{ MECOM-p53.jpg>p53 MECOM-CD71.jpg>CD71 MECOM-E-cadherin.jpg>E-cadherin MECOM-HbF.jpg>HbF染色 MECOM-Fe.jpg>Fe染色 }} Megakaryopoiesis; Mgkは増加している. 多数の分離円形核巨核球が出現している. microMgkが増加している. #gallery(left,nowrap,noadd){{ MECOM-CD42b-01.jpg>CD42b MECOM-CD42b.jpg>CD42b-micro Mgks MECOM-CD42b-02.jpg>CD42b karyotype inv(3)(q1q26).jpg>karyotype GATA2-MECOM-FISH.jpg>GATA2::MECOM FISH }} Myelogram: M/E = 1.77,Blast-M 5.2%, promyelo 7.0%, Myelo 11.4%, Meta 10.0%, Stab 5.4%, Seg 18.8%, Eo mature 0.6%, Ba mature 0.6% Mo 3.0%, Lympho 4.4%, Plasma 0.2 骨髄WT1 R 1.1x10SUP{SIZE(8){4}} ***Acute myeloid leukaemia with MECOM rearrangement [#def54f2c] 臨床的特徴 &color(navy){''ほとんどの患者は細胞減少を呈する''};. しかし白血球増加または血小板増加を伴う場合もある¬e{Rogers:Rogers HJ, et al.Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014 May;99(5):821-9. PMID: 24463215};¬e{Gao:Gao J, et al.Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes Chromosomes Cancer. 2022 Feb;61(2):71-80. doi: 10.1002/gcc.23004. Epub 2021 Oct 28. PMID: 34668265.};。 &color(navy){''ほとんどの患者は細胞減少を呈する''};. しかし白血球増加または血小板増加を伴う場合もある¬e{Rogers:Rogers HJ, et al.Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014 May;99(5):821-9. PMID: 24463215};¬e{Gao:Gao J, et al.Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes Chromosomes Cancer. 2022 Feb;61(2):71-80. doi: 10.1002/gcc.23004. Epub 2021 Oct 28. PMID: 34668265.};. ''通常末梢血芽球は増加する.'' &color(#e2041b){患者の約3分の1は低芽球数を呈する};¬e{Rogers:Rogers HJ, et al.Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014 May;99(5):821-9. PMID: 24463215};¬e{Gao:Gao J, et al.Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes Chromosomes Cancer. 2022 Feb;61(2):71-80. doi: 10.1002/gcc.23004. Epub 2021 Oct 28. PMID: 34668265.};。¬e{:Summerer I, Haferlach C, et al. Prognosis of MECOM (EVI1)-rearranged MDS and AML patients rather depends on accompanying molecular mutations than on blast count. Leuk Lymphoma. 2020 Jul;61(7):1756-1759. doi: 10.1080/10428194.2020.1737689. Epub 2020 Mar 19. PMID: 32189545.};。 ''通常末梢血芽球は増加する.'' &color(#e2041b){患者の約3分の1は低芽球数を呈する};¬e{Rogers:Rogers HJ, et al.Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014 May;99(5):821-9. PMID: 24463215};¬e{Gao:Gao J, et al.Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes Chromosomes Cancer. 2022 Feb;61(2):71-80. doi: 10.1002/gcc.23004. Epub 2021 Oct 28. PMID: 34668265.};。¬e{:Summerer I, Haferlach C, et al. Prognosis of MECOM (EVI1)-rearranged MDS and AML patients rather depends on accompanying molecular mutations than on blast count. Leuk Lymphoma. 2020 Jul;61(7):1756-1759. doi: 10.1080/10428194.2020.1737689. Epub 2020 Mar 19. PMID: 32189545.};. &color(#e2041b){一部の患者で肝脾腫がみられる};ことがある¬e{Rogers:Rogers HJ, et al.Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014 May;99(5):821-9. PMID: 24463215};¬e{Gao:Gao J, et al.Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes Chromosomes Cancer. 2022 Feb;61(2):71-80. doi: 10.1002/gcc.23004. Epub 2021 Oct 28. PMID: 34668265.};。 &color(#e2041b){一部の患者で肝脾腫がみられる};ことがある¬e{Rogers:Rogers HJ, et al.Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014 May;99(5):821-9. PMID: 24463215};¬e{Gao:Gao J, et al.Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation. Genes Chromosomes Cancer. 2022 Feb;61(2):71-80. doi: 10.1002/gcc.23004. Epub 2021 Oct 28. PMID: 34668265.};.
