Overcoming mutational complexity in acute myeloid leukemia by inhibition of critical pathways.
Overcoming mutational complexity in acute myeloid leukemia by inhibition of critical pathways.
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DOI：
10.1126/scitranslmed.aao1214
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发表时间：
2017-10-25
影响因子：
17.1
通讯作者：
Ishikawa F
中科院分区：
文献类型：
--
作者：
Saito Y;Mochizuki Y;Ogahara I;Watanabe T;Hogdal L;Takagi S;Sato K;Kaneko A;Kajita H;Uchida N;Fukami T;Shultz LD;Taniguchi S;Ohara O;Letai AG;Ishikawa F
许多变异等位基因与人类急性髓性白血病（AML）相关。然而，在没有血液病的个体中也发现了相同的变体，使得它们的功能相关性模糊不清。通过NOD.Cg-Prkdcscid//2 rgtmlWjl/Sz（NSG）异种移植，我们在功能上鉴定了FMS样酪氨酸激酶3内部串联重复（FLT 3-ITD）+ AML患者样品中存在的白血病前和白血病干细胞群体。通过单细胞DNA测序，我们确定了克隆结构和与体内命运相关的突变，区分了允许非恶性多系造血的突变和致白血病突变。虽然多体细胞突变在单细胞水平上共存，但抑制与白血病前向白血病干细胞转化密切相关的突变可在体内消除AML。此外，BCL-2的同时抑制揭示了耐药AML细胞对抗凋亡途径的关键依赖性。共同抑制对肿瘤发生和生存至关重要的通路可能是克服人类恶性肿瘤遗传多样性的有效策略。这种将单细胞基因组学与NSG患者来源的异种移植物（PDX）模型相结合的方法可以作为精确靶点鉴定和药物发现的广泛适用的资源。通过功能性单细胞基因组学鉴定的靶向致白血病突变在体内消除了人AML。
Numerous variant alleles are associated with human acute myeloid leukemia (AML). However, the same variants are also found in individuals with no hematological disease, making their functional relevance obscure. Through NOD.Cg-Prkdcscid//2rgtmlWjl/Sz (NSG) xenotransplantation, we functionally identified pre-leukemic and leukemic stem cell populations present in FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)+ AML patient samples. By single-cell DNA sequencing, we identified clonal structures and linked mutations with in vivo fates, distinguishing mutations permissive of non-malignant multilineage hematopoiesis from leukemogenic mutations. Although multiple somatic mutations co-existed at the single-cell level, inhibition of the mutation strongly associated with pre-leukemic to leukemic stem cell transition eliminated AML in vivo. Moreover, concurrent inhibition of BCL-2 uncovered a critical dependence of resistant AML cells on anti-apoptotic pathways. Co-inhibition of pathways critical for oncogenesis and survival may be an effective strategy that overcomes genetic diversity in human malignancies. This approach incorporating single-cell genomics with the NSG patient-derived xenograft (PDX) model may serve as a broadly applicable resource for precision target identification and drug discovery. Targeting leukemogenic mutations identified by functional single cell genomics eliminated human AML in vivo.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
28.2
作者：
Pan R;Hogdal LJ;Benito JM;Bucci D;Han L;Borthakur G;Cortes J;DeAngelo DJ;Debose L;Mu H;Döhner H;Gaidzik VI;Galinsky I;Golfman LS;Haferlach T;Harutyunyan KG;Hu J;Leverson JD;Marcucci G;Müschen M;Newman R;Park E;Ruvolo PP;Ruvolo V;Ryan J;Schindela S;Zweidler-McKay P;Stone RM;Kantarjian H;Andreeff M;Konopleva M;Letai AG
通讯作者：
Letai AG
DOI：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK
SNES：单核外显子组测序。
影响因子：
12.3
作者：
Leung ML;Wang Y;Waters J;Navin NE
通讯作者：
Navin NE
影响因子：
17.1
作者：
Saito, Yoriko;Yuki, Hitomi;Ishikawa, Fumihiko
通讯作者：
Ishikawa, Fumihiko