JP2013519368A - 骨髄性腫瘍の新規診断マーカーとしてのasxl1 - Google Patents
骨髄性腫瘍の新規診断マーカーとしてのasxl1 Download PDFInfo
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Abstract
【選択図】なし
Description
MDSにおける3タイプのaCHGプロファイル
1シリーズの骨髄(BM)サンプルを、MDSに罹患した患者、多系列の異形成を伴うAML(AML−MLD)に罹患した患者、およびCMMLに続発したAMLに罹患した患者から回収した。
MDSサンプル中の複数の候補遺伝子の配列を分析した。
CMMLにおけるASXL1の変異
ASXL1変異がMDS以外に見出される得るかどうかを決定するために、以前に記述したように、CMML(関連疾患)に罹患した患者の骨髄サンプル中のASXL1配列を分析した。
53名の患者(彼らはすべてインフォームドコンセントに署名した)から得られた1シリーズの連続した骨髄サンプルを回収した。FABグループによって最初に定義されたように、それぞれ白血球カウントが13G/Lより多いかまたは少ないかにより、これらの中で31名はMP−CMMLであり、22名はMD−CMMLであった。40名の患者において正常核型が観察され(20名のMP−CMMLおよび20名のMD−CMML);3名の患者(2名のMP−CMMLおよび1名のMD−CMML)においてdel(20q)(q11;q13)が見出され;4名のMP−CMMLにおいて概して影響を受ける染色体(8、19、21)のトリソミーがあった。1名のMD−CMMLには11q逆位があり、1名のMP−CMMLにはt(10;11)(p12;p15)があり、1名のMP−CMMLにはt(1;3)(p36;q21)があった。
MPNにおけるASXL1の変異
ASXL1が他のタイプの骨髄疾患に関与するかどうかを決定するために、64例の骨髄増殖性腫瘍(MPN)中のASXL1遺伝子を研究した。
先の分析は、97例のPV、ETおよびMF、9例の急性期PV/ET/MF、ならびに6例の未分類のMPNおよびMPN/MDS形態を含む、新規MPNの112症例について行われた。10例の反応性血小板増加症(RT)および22例の反応性赤血球増加症(RE)を含む、非MPNの32症例における変異についても調査した。
ASXL1がAMLに関与するかどうかを決定するために、先に記述されるようなDNAシークエンシングおよびaCGHを使用して、AMLの正常核型を持つ46症例、および単独の核型異常として8トリソミー(n=14)、9q欠失(HD−0632)、11トリソミー(HD−0304)または20q11−13欠失(HD−0381)を持つ17症例における遺伝子の変異および欠失について検索した。
患者はすべてインフォームドコンセントに署名し、研究は施設内倫理委員会によって承認された。それらはMDSの65症例を含む。WHOの基準に従って、パネルは5例の不応性貧血(RA)、13例の輪状鉄芽球を伴う不応性貧血(RARS)(骨髄線維症を伴う1例を含む)、7例の多系列の異形成を伴う難治性血球減少(RCMD)、16例の芽球増加型不応性貧血1型(RAEB1)、19例の芽球増加型不応性貧血2型(RAEB2)および5例のMDS未分類の(MDS−U)症例を含んでいた。6症例が造血系疾患または非造血系疾患に続発していた。大部分MDSのサンプルは診断時に回収され;いくつかは既知のMDSの治療回避中であり、いくつかは対症療法下であった。17症例はIPPS低リスク(0)、23症例は中間−1(0.5〜1)、12症例は中間−2(1.5〜2)、および7症例は高リスク(>2.5)であった。
Claims (47)
- 被験体における骨髄性癌を診断する方法であって、該方法は、配列番号:2の配列を有するポリペプチドをコードするASXL1(additional sex combs様1)遺伝子中の変異の存在または非存在の決定によって該被験体からの生物学的サンプルを分析する工程であって、かかる変異の存在を骨髄性癌と相関させる、工程を含む、方法。
- 前記被験体がヒトである、請求項1に記載の方法。
- 前記骨髄性癌が、骨髄異形成症候群(MDS)、骨髄異形成/骨髄増殖性疾患、骨髄増殖性腫瘍(MPN)および急性骨髄性白血病(AML)から選択される、請求項1に記載の方法。
- 前記方法が被験体における骨髄異形成症候群(MDS)を診断するためのものである、請求項3に記載の方法。
- 前記方法が芽球増加型不応性貧血2型(RAEB2)の診断のためのものである、請求項4に記載の方法。
- 前記方法が骨髄異形成/骨髄増殖性疾患の診断のためのものである、請求項3に記載の方法。
- 前記方法が被験体における慢性骨髄単球性白血病(CMML)を診断するためのものである、請求項6に記載の方法。
- 前記CMMLがCMML(MP CMML)の骨髄増殖性形態である、請求項7に記載の方法。
- 前記方法がMP−CMMLをMD−CMMLから鑑別するためのものある、請求項8に記載の方法。
- 前記方法が被験体における骨髄増殖性腫瘍(MPN)を診断するためのものある、請求項3に記載の方法。
- 前記MPNが原発性骨髄線維症(PMF)である、請求項10に記載の方法。
- 前記MPNが真性多血症後骨髄線維症(PV後MF)である、請求項10に記載の方法。
- 前記MPNが本態性血小板血症後骨髄線維症(ET後MF)である、請求項10に記載の方法。
- 前記MPNが本態性血小板血症(ET)であり、ASXL1遺伝子中の変異の存在が反応性血小板増加症を除外する、請求項10に記載の方法。
- 前記方法が被験体における急性骨髄性白血病(AML)を診断するためのものである、請求項3に記載の方法。
- 前記AMLが続発性AMLである、請求項15に記載の方法。
- 前記続発性AMLが慢性骨髄疾患に後続する、請求項16に記載の方法。
- 前記生物学的サンプルが骨髄サンプルである、請求項1に記載の方法。
- 前記変異が、挿入、欠失、ならびにミスセンス変異およびナンセンス変異に対応する点変異から選択される、請求項1に記載の方法。
- 前記変異が、挿入、欠失およびナンセンス変異を含む、請求項1に記載の方法。
- 前記変異が変異したASXL1タンパク質の発現をもたらし、該変異したASXL1タンパク質がPHDドメイン(配列番号:3)またはその断片を含まない、請求項1に記載の方法。
- 前記変異が、ASXL1タンパク質のオープンリーディングフレームにおいて終止コドン(X)の導入をもたらすナンセンス変異である、請求項21に記載の方法。
- 前記変異が、Tyr591X、Gln592X、Lys618X、Arg693X、Gln759X、Gln768X、Leu775XおよびArgl068Xを含む群において選択されるナンセンス変異である、請求項22に記載の方法。
- 前記変異したタンパク質が、ASXL1遺伝子中への欠失の挿入に起因するフレームシフト(FS)に由来する、請求項21に記載の方法。
- 前記変異が、Gly64Trp FS、Arg596Pro FS、Ala611Arg FS、His630Pro FS、Gly646Trp FS、Leu762Phe FS、Trp796Gly FS、Thr822Asn FS、Thr836Leu FS、Ser846Gln FS、Asp879Glu FS、Lys888Glu FS、Leu1213Ile FS、Pro1263Gln FS、Leu1266His FS、Trp1271 Lys FS、またはSer1457Pro FSを含む群において選択された変異を有する変異したASXL1タンパク質の発現を誘導する挿入または欠失である、請求項24に記載の方法。
- 前記決定工程がゲノムDNA上で行われる、請求項1に記載の方法。
- 前記決定工程がASXL1 mRNA/cDNA上で達成される、請求項1に記載の方法。
- 前記決定工程がASXL1タンパク質上で達成される、請求項1に記載の方法。
- 少なくとも1つの核酸プローブもしくはオリゴヌクレオチドまたは少なくとも1つの抗体を含む被験体における骨髄性癌の診断のためのキットであって、配列番号:2の配列を有するポリペプチドをコードするASXL1(additional sex combs様1)遺伝子中の変異の存在または非存在を決定し、かかる変異の存在を骨髄性癌と相関させるための、請求項1〜28のいずれか一項において定義される方法において使用することができるキット。
- 前記オリゴヌクレオチドが、ASXL1遺伝子またはその断片の増幅を可能にする少なくとも1つのPCRプライマー、好ましくはPCRプライマーのセットである、請求項29に記載のキット。
- 前記骨髄性癌が、骨髄異形成症候群(MDS)、骨髄異形成/骨髄増殖性疾患、骨髄増殖性腫瘍(MPN)および急性骨髄性白血病(AML)からなる群において選択される、請求項29に記載のキット。
- 被験体における骨髄性癌の予後を評価する方法であって、該方法は、配列番号:2の配列を有するポリペプチドをコードするASXL1(additional sex combs様1)遺伝子中の変異の存在または非存在の決定によって該被験体からの生物学的サンプルを分析する工程であって、変異の存在は該患者の予後不良を示し、変異の非存在は該患者の予後良好を示唆する、工程を含む方法。
- 前記骨髄性癌がMDSであり、本発明の方法が該MDSの不応性貧血への進行の予後のためのものである、請求項32に記載の方法。
- 前記不応性貧血が芽球増加型不応性貧血2型(RAEB)である、請求項33に記載の方法。
- 前記ASXL1遺伝子中の変異がGly646Trp FSである、請求項33に記載の方法。
- 前記骨髄性癌がMDSであり、本発明の方法が該MDSのAMLへの進行の予後のためのものであり、ASXL1変異の存在がかかるリスク進行を示す、請求項32に記載の方法。
- 前記AMLが続発性貧血である、請求項36に記載の方法。
- 前記骨髄性癌がCMMLであり、本発明の方法が該CMMLのAMLへの進行の予後のためのものである、請求項32に記載の方法。
- 前記ASXL1遺伝子中の変異がGly646Trp FSである、請求項38に記載の方法。
- 前記CMMLがMP−CMMLである、請求項38に記載の方法。
- 前記骨髄性癌がCMMLであり、本発明の方法が前記患者のための転帰の予後のためのものである、請求項32に記載の方法。
- ASXL1変異の存在が転帰不良と関連する、請求項41に記載の方法。
- 前記骨髄性癌が真性多血症(PV)であり、本発明の方法が該PVの真性多血症後骨髄線維症(PV後MF)への進行の予後のためのものである、請求項32に記載の方法。
- 前記本態性血小板血症(ET)および本発明の方法が前記PVの本態性血小板血症後骨髄線維症(ET後MF)への進行の予後のためのものである、請求項32の記載の方法。
- 被験体における骨髄性癌のための治療への応答を予測する方法であって、配列番号:2の配列を有するポリペプチドをコードするASXL1(additional sex combs様1)遺伝子中の変異の存在または非存在の決定によって該被験体からの生物学的サンプルを分析する工程を含む方法。
- 前記変異が後成的修飾をもたらす、請求項45に記載の方法。
- 前記治療が脱メチル化剤およびHDAC阻害剤を含む1つまたは複数の薬物を使用する、請求項45に記載の方法。
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US9375485B2 (en) | 2012-12-07 | 2016-06-28 | Geron Corporation | Use of telomerase inhibitors for the treatment of myeloproliferative disorders and myeloproliferative neoplasms |
WO2016030914A1 (en) | 2014-08-27 | 2016-03-03 | Hampidjan Hf. | Line for a signal buoy and methods for submerged object retrieval and monitoring |
JP2017533714A (ja) * | 2014-11-12 | 2017-11-16 | ネオゲノミクス ラボラトリーズ, インコーポレイテッド | 末梢血血漿dnaのディープシーケンシングは、骨髄異形成症候群の診断を確認するうえで信頼性が高い |
WO2016207405A1 (en) * | 2015-06-25 | 2016-12-29 | Institut Gustave-Roussy | Prognostic marker for myeloproliferative neoplasms |
WO2019113269A1 (en) * | 2017-12-08 | 2019-06-13 | Kura Oncology, Inc. | Methods of treating cancer patients with farnesyltransferase inhibitors |
WO2021099573A1 (en) * | 2019-11-21 | 2021-05-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for diagnosing and treating chronic myelomonocytic leukemia (cmml) |
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