WO2009084525A1 - 白血病細胞の検出方法 - Google Patents
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- WO2009084525A1 WO2009084525A1 PCT/JP2008/073393 JP2008073393W WO2009084525A1 WO 2009084525 A1 WO2009084525 A1 WO 2009084525A1 JP 2008073393 W JP2008073393 W JP 2008073393W WO 2009084525 A1 WO2009084525 A1 WO 2009084525A1
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- G—PHYSICS
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57426—Specifically defined cancers leukemia
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
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- the present invention relates to a method for detecting leukemia, particularly acute leukemia, and a kit used for detecting leukemia.
- Leukemia is a disease that belongs to a malignant tumor of blood, in which tumoriated hematopoietic cells proliferate indefinitely and appear in the blood. Some erythrocyte and platelet cells have become tumors, but many are leukocyte cells that have become tumors. These diseases are collectively called leukemia.
- leukemia when the differentiation is stopped at a certain stage of blood cell differentiation or maturation and undifferentiated blast cells upstream from it grow to constitute a tumor, the biological regulatory ability May show autonomous growth but retain the ability to differentiate or mature, the former being acute leukemia, the latter being chronic leukemia or myelodysplastic syndrome (MDS). Applicable. Many of the causes and pathogenesis of leukemia are unknown, but early detection and treatment are extremely important for treatment.
- Leukemia is diagnosed by morphological observation of blood cells, chromosomal examination, or surface antigen analysis of blood cells using flow cytometry. For leukemia with chromosomal or genetic abnormalities, PCR or RT-PCR using disease-specific primers is also performed. Furthermore, it has been reported that the results of quantitative RT-PCR of Wilms tumor gene 1 (WT-1) reflect the amount of tumor cells in leukemia (Non-patent Document 1).
- MRD micro residual tumor
- An object of the present invention is to provide a simple and accurate method for detecting leukemia or leukemia cells that is quantitative and has few false positives using a selective marker for leukemia, particularly acute leukemia.
- the present inventors have found that the expression of DOCK180 observed in normal CD34-positive cells tends to decrease or disappear in tumorized CD34-positive cells with respect to leukemia in which CD34-positive cells have become tumorous. Based on the above, the following inventions have been completed.
- a method for detecting leukemia cells comprising detecting CD34-positive cells whose DOCK180 expression is negative in a blood sample.
- a kit for detecting leukemia cells comprising an anti-DOCK180 antibody.
- kit according to (5) further comprising an anti-CD34 antibody.
- (7) including detecting CD34-positive cells having negative expression of DOCK180 in a blood sample, and measuring a ratio of CD34-positive cells having negative expression of DOCK180 to CD34-positive cells having normal expression of DOCK180.
- the CD34 positive cells in which the expression of DOCK180 is normal and the CD34 positive cells in which the expression of DOCK180 is negative are detected by immunological detection using an anti-CD34 antibody and an anti-DOCK180 antibody. The inspection method described.
- a kit for testing the degree of progression or recovery of leukemia comprising an anti-DOCK180 antibody.
- test kit according to (11), further comprising an anti-CD34 antibody.
- a method for detecting leukemia comprising measuring the expression level of DOCK180 in CD34-positive cells in a blood sample.
- a kit for detecting leukemia comprising a nucleic acid that hybridizes to an anti-DOCK180 antibody or DNA encoding DOCK180.
- a method for examining the degree of progression or regression of leukemia comprising measuring the expression level of DOCK180 in CD34-positive cells in a blood sample.
- the expression level of DOCK180 in CD34-positive cells in a blood sample is measured using the expression level of DOCK180 in CD34-positive cells in a healthy blood sample as an index value, or the progression or regression of leukemia according to (19) How to check the degree.
- the present invention confirms the specific expression pattern of DOCK180 on tumor cells of leukemia, particularly acute leukemia, so that information useful for diagnosing leukemia by a doctor and examining and diagnosing the severity and recovery degree of leukemia. Can be obtained and provided for blood samples by a simple method.
- DOCK180 mRNA in 293T cells measured by quantitative RT-PCR is 1000 units, 3 cases of initial CD34-positive acute lymphoblastic leukemia (ALL), 4 cases of recurrent CD34-positive ALL, 4 cases of initial CD34 14 cases of positive acute myeloid leukemia (AML), 2 cases of recurrent CD34 positive AML, 2 cases of recurrent CD34 positive chronic myeloid leukemia (CML), 2 cases, total of 25 tumor cells It is the table
- the present invention uses, as an element, confirmation, detection, or quantification of DOCK180 expression in CD34-positive cells in a blood sample, that is, using the expression of DOCK180 protein or a gene encoding it as a diagnostic marker for leukemia It is invention regarding the method to do.
- One embodiment of the present invention is a method for detecting leukemia cells, which comprises detecting CD34-positive cells in which DOCK180 expression is negative in a blood sample.
- the expression of DOCK180 tends to decrease or disappear compared to normal CD34 positive cells. This means that it is possible to determine that a CD34-positive cell with negative expression of DOCK180 is a tumorigenic cell. Therefore, the results in the method of the present invention that such tumorized CD34 positive cells were detected in blood samples, particularly bone marrow fluid samples, helped physicians determine whether the samples were suffering from leukemia. It will be useful information.
- Another aspect of the present invention is to detect CD34-positive cells in which expression of DOCK180 is negative in a blood sample, particularly bone marrow fluid sample, and to express CD34 in which expression of DOCK180 is negative with respect to CD34-positive cells in which expression of DOCK180 is normal.
- This is a method for examining the degree of progression or regression of leukemia, including measuring the ratio of positive cells.
- the measurement result regarding the proportion of CD34 cells in which the expression of DOCK180 is negative in the total number of CD34 positive cells contained per unit volume of a blood sample, particularly a bone marrow fluid sample shows the degree of progression or regression of leukemia in the sample. It is a more useful and objective judgment material for doctors to diagnose the severity and recovery of leukemia in patients.
- the present invention provides a method for detecting leukemia, comprising measuring the expression level of DOCK180 in CD34-positive cells in a blood sample, particularly a bone marrow sample.
- This method measures, for example, the expression level of DOCK180 in the whole CD34-positive cells in a unit volume, instead of detecting CD34-positive cells in which the expression of DOCK180 is negative in a blood sample, particularly a bone marrow fluid sample.
- the measured value is decreased or increased after decrease when the expression level of DOCK180 in CD34-positive cells of a healthy sample is used as an index value.
- the expression of DOCK180 is negative in the tested sample. It means that CD34 positive cells or cells with normal expression of DOCK180 are included.
- results provide a material for physicians to determine whether a patient is suffering from leukemia or is in remission. That is, the degree of progression and regression of leukemia can be examined by quantitatively measuring the degree of expression level of DOCK180 in CD34 positive cells.
- the test result is a more useful and objective judgment material for the doctor to diagnose the severity of leukemia or recovery of the patient.
- the “blood sample” in the present invention refers to bone marrow fluid, peripheral blood collected from veins, and centrifugation according to the method described in Nishio et al. (Blood, 2005, 106, 1012-1020). It is a term encompassing a blood cell fraction specimen containing CD34-positive cells by performing a known chemical treatment in preparation of treatment and blood cell fraction.
- a preferred embodiment of the blood sample in the present invention is bone marrow fluid, and a particularly preferred embodiment is a blood cell fraction sample fractionated from bone marrow fluid.
- CD34 positive cells are hematopoietic progenitor cells that highly express the glycoprotein CD34 on the surface of the cells.
- CD34-positive cells are contained in blood, particularly umbilical cord blood, bone marrow fluid, and the like. From these, detection or detection is performed according to the method described in Nishio et al. (Exp. Hematology, 2001, Vol. 29, pp. 19-29). Can be separated.
- the CD34-positive cells a device for separating the blood or the like, for example, can also be separated using the Isolex TM 300i (Takara Bio).
- DOCK180 is a type of protein that controls the growth of higher eukaryotic cells that binds to the Crk protein, which is an expression product of a pre-oncogene.
- DOCK180 is also known as one of guanine nucleotide exchange factors called Rac, which activate low molecular weight G protein (Guaninenuclide ExchangeGFactor, GEF).
- GEF Guaninenuclide ExchangeGFactor
- DOCK180 protein Since it has been clarified that the binding between Crk protein and DOCK180 activates cell proliferation ability, DOCK180 protein has attracted attention as a diagnostic index for cancer cells expressing Crk protein and as a target for missile therapy with various anticancer agents. It had been.
- the present inventors have found that unlike conventional reports, many of the leukemia cells, particularly cells in which CD34 positive cells are tumorized, are tumor cells in which the expression of DOCK180 is negative.
- DOCK180 is negative in CD34 cells according to the present invention means that the expression of DOCK180 is reduced or eliminated, specifically, a general technique for confirming the expression of genes and proteins, for example, immunology Even when genetic detection techniques such as hybridization or PCR are used with normal sensitivity, DOCK180 protein or mRNA encoding DOCK180 cannot be confirmed in CD34 positive cells, or normal CD34 positive cells
- the expression level of DOCK180 protein or mRNA encoding DOCK180 is 50% or less, preferably 30% or less, more preferably 10% or less, still more preferably 5% or less, based on the expression level of DOCK180 in In the sense of including That.
- the normal expression of DOCK180 in normal CD34 positive cells and CD34 cells referred to in the present invention means that the CD34 cells not affected by leukemia, that is, not tumorigenic, and the CD34 positive cells express DOCK180. It means the state or its expression level.
- the leukemia or leukemia cell in the present invention may be any of acute leukemia (including both myeloid and lymphoid), chronic leukemia (chronic myelogenous leukemia, chronic myeloid leukemia; CML), chronic lymphocytic leukemia (chronic leukemia, CLL). ), Leukemia such as erythroleukemia, or platelet blood disease and tumor cells thereof, myelodysplastic syndrome (MDS) and its cells, particularly acute myelogenous leukemia (acte myeloid leukemia; AML), Acute lymphoblastic leukemia (ALL) and leukocyte that has become tumor.
- acute leukemia including both myeloid and lymphoid
- chronic leukemia chronic myelogenous leukemia, chronic myeloid leukemia; CML
- chronic lymphocytic leukemia chronic leukemia, CLL
- Leukemia such as erythroleukemia, or platelet blood disease and tumor cells thereof, myelody
- the means for detecting or measuring the expression level of DOCK180 in the method of the present invention is a means capable of accurately detecting or quantifying the amount of mRNA encoding DOCK180 protein and / or DOCK180 in CD34 positive cells.
- an anti-DOCK180 protein antibody particularly a combination of an anti-DOCK180 antibody and an anti-CD34 protein antibody.
- antibodies polyclonal antibodies, monoclonal antibodies, Fab fragments and other biomolecules understood by those skilled in the art as “antibodies” can be used. The use of monoclonal antibodies is particularly preferred.
- the antibody used in the present invention using an immunological detection means is preferably labeled with a labeling substance.
- the labeling substance is a substance that provides a detectable signal by reacting the labeling substance alone or with another substance, such as horseradish peroxidase, alkaline phosphatase, ⁇ -D-galactosidase, glucose oxidase , Glucose-6-phosphate dehydrogenase, alcohol dehydrogenase, malate dehydrogenase, penicillinase, catalase, apoglucose oxidase, urease, luciferase or acetylcholinesterase, fluorescein isothiocyanate, phycobiliprotein, rare earth metal chelate , dansyl chloride or fluorescent substances such as tetramethylrhodamine isothiocyanate, 125 I, 14 C, 3 H radioisotopes such as, biotin, avidin Wakashi It
- non-adherent antibody was removed by centrifugation, resuspended in 200 ⁇ L of the medium, and analysis was performed using FACSCalibur (BD Biosciences) and BD CellQuest TM Proversion 5.2 (BD Biosciences).
- FACSCalibur BD Biosciences
- BD CellQuest TM Proversion 5.2 BD Biosciences
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Abstract
Description
組み換え型ヒト顆粒コロニー刺激因子(recombinant human granulocyte colony stimulatory factor、以下、rhG-CSFと表す)は中外製薬から購入した。インターロイキン-3(Interleukin-3、以下、IL-3と表す)及び幹細胞因子(stem cell factor、以下、SCFと表す)はPeproTechから購入した。フィコエリスリン(phycoerythrin、以下、PEと表す)標識抗ヒトCD14抗体はBeckman Coulterから、フルオレセイン-イソチオシアネート(fluorescein-isothiocyanate、以下、FITCと表す)標識抗ヒトCD34抗体はBD Biosciencesから購入した。またネガティブコントロールは、それに対応するクラスの抗体をDakoCytomationから購入した。抗DOCK180抗体、ヤギ抗マウスIgG-HRP抗体及びヤギ抗ウサギIgG-HRPはSanta Cruz Biotechnologyから、抗β-アクチン(β-actin)抗体はSIGMA-ALDRICHからそれぞれ購入した物を使用した。
(1)単核細胞の回収およびヒトCD34陽性細胞の回収
倫理規定に基づいた同意を得て採取した健常人の骨髄液と末梢血それぞれから、Ficoll-Hypaque(Amersham)を用いた比重遠心法で、骨髄液由来の単核細胞(BM-MNC)と末梢血由来の単核細胞(PB-MNC)を分離した。また、倫理規定に基づいた同意を得た健常人成人に5μg/kgのrhG-CSFを5日間連日皮下投与して、ヒトCD34陽性細胞を動員した後に末梢血を採取し、血球分離装置を用いて白血球画分を回収し、液体窒素を用いて凍結保存した。以下、回収した白血球画分をアフェレーシスプロダクト(AP)と表す。さらに、凍結保存したAPから、比重遠心法で単核細胞(AP-MNC)を分離した。
(1)で回収したBM-CD34、AP-CD34及び急性骨髄性白血病と診断された患者の骨髄血由来のCD34陽性細胞(AML-CD34)それぞれを、0.5%牛血清アルブミンを添加したdeficient RPMI1640培地(SIGMA-ALDRICH)に1×106細胞/mLの濃度で懸濁させた後、20μg/mLのPE抗ヒトCD14抗体、20μg/mLのFITC抗ヒトCD34抗体及びそれぞれの抗体に対するマウスIgG1 negative controlを加えて氷上で30分間反応させた。反応後、遠心分離にて非付着抗体を除去し、200μLの前記培地に再懸濁させ、FACSCalibur(BD Biosciences)とBD CellQuestTM Pro version5.2(BD Biosciences)を用いて、解析を行った。その結果、純化後のBM-CD34、AP-CD34のヒトCD34陽性細胞率は、いずれも90%以上であった。またAML-CD34のCD34陽性細胞率は70%以上であった。
(1)で得たPB-MNC、GC、AP-MNC、AP-CD34、BM-MNC及びBM-CD34の各細胞5×106個から、RNeasy Mini Kit(QIAGEN)を用いて全RNAを抽出した。これをRQ1 RNase free DNase1(Promega)で処理後、SuperScriptTM First-Strand Synthesis System for RT-PCR(Invitrogen)を用いてcDNAを合成した.得られたcDNA6μLをヒトDOCK180あるいはグリセルアルデヒド3リン酸脱水素酵素(GAPDH)に対する特異的プライマー(TaqMan Gene Expression Assays、Applied Biosystems)とTaqMan Universal PCR Master Mix(Applied Biosystems)とを全量25μLで混和し、初期変性(95℃、10分間)後、95℃で15秒間、60℃で1分間を1サイクルとするPCR反応を40サイクル行った。各サンプルのDOCK180mRNAの発現量はGAPDHのmRNAの発現量で補正し、293T細胞の発現量を1000 unitsに規定して、それに対する相対量として数値化した。
(3)のAP-CD34、BM-CD34、AP-MNC及びBM-MNC同じ各細胞種を、1%NP-40を含有するlysis bufferで溶解後、14000rpm、4℃で15分間遠心して上清を回収し、蛋白抽出液とした。各サンプルを7.5~15%のポリアクリルアミノグラジエントゲル(BIO-RAD)を用いたSDS-PAGEにより電気泳動後、泳動パターンをニトロセルロース膜(PALL)に転写した。転写された膜を、5%スキムミルクを添加した1%Tween-phosphate buffered salineで30分間ブロッキング後、各一次抗体と室温で2時間反応させた。一次抗体には抗DOCK180抗体及び抗β-アクチン抗体を用いた。膜を洗浄後、それぞれに対応する二次抗体と室温で30分間反応させ、ECL Western blotting detection reagent(Amersham)を用いて発色させ、LAS1000(Fujifilm)にて画像化した。
新規発症(初発)のCD34陽性ALL症例3例、再発のCD34陽性ALL症例4例、初発のCD34陽性AML症例14例、再発のCD34陽性AML症例2例及び再発CD34陽性CML急性転化症例2例、合計25例の骨髄液を、倫理規定に基づいた患者の同意を得て採取し、この細胞から全RNAを抽出し、前記(3)同様の定量RT-PCR法でDOCK180mRNAの発現量を検討した。その結果を図3及び図4に示す。
診断時に骨髄穿刺を行った結果としてCD34陽性急性骨髄性白血病症と診断された患者に対して、イダマイシンとキロサイドからなる寛解導入治療を7日間行った。寛解導入治療前は、前記患者の骨髄は80%以上の白血病細胞で占められており、その全てがCD34陽性であった。この骨髄細胞のDOCK180を前記と同様にして測定した。また、血球の回復期の骨髄穿刺を指標として一定の治療効果が認められた患者から骨髄液検体を採取し、前記と同様にして、寛解期CD34陽性細胞におけるDOCK180の発現量を定量的RT-PCRで測定した。その結果、白血病に対するイダマイシンとキロサイドからなる寛解導入治療によって寛解した患者のCD34陽性細胞においてDOCK180が発現していることが確認された(図5)。
Claims (22)
- 血液検体においてDOCK180の発現が陰性であるCD34陽性細胞を検出することを含む、白血病細胞の検出方法。
- 抗CD34抗体と抗DOCK180抗体を用いた免疫学的検出法によってDOCK180の発現が陰性であるCD34陽性細胞を検出する、請求項1に記載の白血病細胞の検出方法。
- 白血病細胞が急性白血病細胞である、請求項1又は2に記載の白血病細胞の検出方法。
- 急性白血病細胞が急性リンパ性白血病細胞である、請求項3に記載の白血病細胞の検出方法。
- 抗DOCK180抗体を含む、白血病細胞検出用キット。
- さらに抗CD34抗体を含む、請求項5に記載のキット。
- 血液検体においてDOCK180の発現が陰性であるCD34陽性細胞を検出し、DOCK180の発現が正常なCD34陽性細胞に対する前記DOCK180の発現が陰性であるCD34陽性細胞の比率を測定することを含む、白血病の進行度又は退行度を検査する方法。
- 抗CD34抗体と抗DOCK180抗体を用いた免疫学的検出法によって、DOCK180の発現が正常であるCD34陽性細胞とDOCK180の発現が陰性であるCD34陽性細胞の検出を行う、請求項7に記載の検査方法。
- 白血病が急性白血病である、請求項7又は8に記載の検査方法。
- 急性白血病が急性リンパ性白血病である、請求項9に記載の検査方法。
- 抗DOCK180抗体を含む、白血病の進行度又は回復度の検査用キット。
- さらに抗CD34抗体を含む、請求項11に記載の検査用キット。
- 血液検体中のCD34陽性細胞におけるDOCK180の発現量を測定することを含む、白血病の検出方法。
- 健常な血液検体中のCD34陽性細胞におけるDOCK180の発現量を指標値として、血液検体中のCD34陽性細胞におけるDOCK180の発現量を測定する、請求項13に記載の白血病の検出方法。
- 白血病が急性白血病である、請求項13又は14に記載の白血病の検出方法。
- 急性白血病が急性リンパ性白血病である、請求項15に記載の白血病の検出方法。
- 抗DOCK180抗体又はDOCK180をコードするDNAにハイブリダイズする核酸を含む、白血病検出用キット。
- さらに抗CD34抗体を含む、請求項17に記載のキット。
- 血液検体中のCD34陽性細胞におけるDOCK180の発現量を測定することを含む、白血病の進行度又は退行度を検査する方法。
- 健常な血液検体中のCD34陽性細胞におけるDOCK180の発現量を指標値として、血液検体中のCD34陽性細胞におけるDOCK180の発現量を測定する、請求項19に記載の白血病の進行度又は退行度を検査する方法。
- 白血病が急性白血病である、請求項19又は20に記載の白血病の進行度又は退行度を検査する方法。
- 急性白血病が急性リンパ性白血病である、請求項21に記載の白血病の進行度又は退行度を検査する方法。
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ES2157227T3 (es) * | 1993-02-09 | 2001-08-16 | Becton Dickinson Co | Asignacion automatica del linaje de leucemias agudas mediante citometria de flujo. |
WO2003085399A1 (fr) * | 2002-04-09 | 2003-10-16 | Tokai University | Methode de determination d'une leucemie, d'une preleucemie ou d'une maladie sanguine maligne aleucemique, et methode diagnostique |
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2008
- 2008-12-24 WO PCT/JP2008/073393 patent/WO2009084525A1/ja active Application Filing
- 2008-12-24 US US12/735,274 patent/US8617804B2/en not_active Expired - Fee Related
- 2008-12-24 JP JP2009548036A patent/JP5371778B2/ja not_active Expired - Fee Related
- 2008-12-24 EP EP08868616A patent/EP2241892B1/en not_active Not-in-force
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Also Published As
Publication number | Publication date |
---|---|
EP2241892B1 (en) | 2012-08-08 |
JP5371778B2 (ja) | 2013-12-18 |
JPWO2009084525A1 (ja) | 2011-05-19 |
EP2241892A1 (en) | 2010-10-20 |
US20110014636A1 (en) | 2011-01-20 |
US8617804B2 (en) | 2013-12-31 |
EP2241892A4 (en) | 2010-12-22 |
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