Combined proteomics and CRISPR-Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo

被引：13

作者：

Bahrami, Ehsan ^{[1
]}

Schmid, Jan Philipp ^{[1
,2
]}

Jurinovic, Vindi ^{[1
,3
]}

Becker, Martin ^{[1
]}

Wirth, Anna-Katharina ^{[1
]}

Ludwig, Romina ^{[1
,2
]}

Kreissig, Sophie ^{[4
]}

Duque Angel, Tania Vanessa ^{[1
]}

Amend, Diana ^{[1
]}

Hunt, Katharina ^{[1
]}

Oellinger, Rupert ^{[5
,6
,7
]}

Rad, Roland ^{[2
,5
,6
,7
]}

Frenz, Joris Maximilian ^{[8
,9
,10
]}

Solovey, Maria ^{[11
,12
]}

Ziemann, Frank ^{[3
]}

Mann, Matthias ^{[13
]}

Vick, Binje ^{[1
,2
]}

Wichmann, Christian ^{[4
]}

Herold, Tobias ^{[1
,2
,3
]}

Jayavelu, Ashok Kumar ^{[8
,9
,10
,13
]}

Jeremias, Irmela ^{[1
,2
,14
]}

机构：

[1] Helmholtz Ctr Munich, Res Unit Apoptosis Hematopoiet Stem Cells, Feodor Lynen Str 21, D-81377 Munich, Germany

[2] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany

[3] Ludwig Maximilians Univ Munchen, LMU Univ Hosp, Dept Med 3, Lab Expt Leukemia & Lymphoma Res ELLF, Munich, Germany

[4] Ludwig Maximilians Univ Munchen, LMU Univ Hosp, Div Transfus Med Cell Therapeut & Haemostaseol, Munich, Germany

[5] Tech Univ Munich, Ctr Translat Canc Res TranslaTUM, TUM Sch Med, Klinikum Rechts Isar, Munich, Germany

[6] Tech Univ Munich, Dept Med 2, Klinikum Rechts Isar, Munich, Germany

[7] Tech Univ Munich, Inst Mol Oncol & Funct Genom, Munich, Germany

[8] German Canc Res Ctr, Prote & Canc Cell Signaling Grp, Heidelberg, Germany

[9] Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[10] Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany

[11] Helmholtz Ctr Munich, Inst Computat Biol, Munich, Germany

[12] Ludwig Maximilians Univ Munchen, Fac Med, Chair Physiol Chem, Biomed Ctr BMC, Munich, Germany

[13] Max Planck Inst Biochem, Dept Prote & Signal Transduct, Munich, Germany

[14] Ludwig Maximilians Univ Munchen, LMU Univ Hosp, Dr Von Hauner Childrens Hosp, Dept Pediat, Munich, Germany

来源：

MOLECULAR CANCER | 2023年 / 22卷 / 01期

基金：

欧盟地平线“2020”; 欧洲研究理事会;

关键词：

CRISPR-Cas9 in vivo screen; Proteomics; ADAM10; PDX; Acute leukemia; Leukemia stem cells; ACUTE LYMPHOBLASTIC-LEUKEMIA; STEM-CELLS; XENOGRAFT MODELS; CANCER; EXPRESSION; CXCR4; SYSTEM; FAMILY;

D O I：

10.1186/s12943-023-01803-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

BackgroundAcute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells.MethodsTo identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR-Cas9 pipeline in PDX models in vivo.ResultsA disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo.ConclusionsThese findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias.

引用

页数：19

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