iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia

被引：15

作者：

Dannenmann, Benjamin ^{[1
]}

Klimiankou, Maksim ^{[1
]}

Oswald, Benedikt ^{[1
]}

Solovyeva, Anna ^{[1
]}

Mardan, Jehan ^{[1
]}

Nasri, Masoud ^{[1
]}

Ritter, Malte ^{[1
]}

Zahabi, Azadeh ^{[1
]}

Arreba-Tutusaus, Patricia ^{[1
]}

Mir, Perihan ^{[1
]}

Stein, Frederic ^{[1
]}

Kandabarau, Siarhei ^{[2
]}

Lachmann, Nico ^{[3
]}

Moritz, Thomas ^{[3
]}

Morishima, Tatsuya ^{[1
]}

Konantz, Martina ^{[4
]}

Lengerke, Claudia ^{[5
]}

Ripperger, Tim ^{[5
]}

Steinemann, Doris ^{[5
]}

Erlacher, Miriam ^{[6
,7
,8
]}

Niemeyer, Charlotte M. ^{[6
,7
,8
]}

Zeidler, Cornelia ^{[9
]}

Welte, Karl ^{[10
]}

Skokowa, Julia ^{[1
]}

机构：

[1] Univ Hosp Tuebingen, Dept Oncol Hematol Immunol & Rheumatol, D-72074 Tubingen, Germany

[2] Dr Margarete Fischer Bosch Inst Clin Pharmacol IK, D-70376 Stuttgart, Germany

[3] Hannover Med Sch, Inst Expt Hematol, D-30625 Hannover, Germany

[4] Univ Hosp Basel, Dept Biomed, CH-4031 Basel, Switzerland

[5] Hannover Med Sch, Inst Human Genet, D-30625 Hannover, Germany

[6] Univ Freiburg, Fac Med, Div Pediat Hematol & Oncol Med Ctr, Dept Pediat & Adolescent Med, D-79106 Freiburg, Germany

[7] German Canc Consortium DKTK, D-79106 Freiburg, Germany

[8] German Canc Res Ctr, D-69120 Heidelberg, Germany

[9] Hannover Med Sch, Dept Oncol Hematol Immunol & Bone Marrow Transpla, D-39625 Hannover, Germany

[10] Univ Childrens Hosp Tuebingen, D-72074 Tubingen, Germany

来源：

CELL STEM CELL | 2021年 / 28卷 / 05期

关键词：

BONE-MARROW FAILURE; PLURIPOTENT STEM-CELLS; ACUTE MYELOID-LEUKEMIA; STIMULATING-FACTOR-RECEPTOR; CSF3R MUTATIONS; RUNX1; MUTATIONS; MYELODYSPLASTIC SYNDROME; CONNECTIVITY MAP; GENE; DIFFERENTIATION;

D O I：

10.1016/j.stem.2021.03.023

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndrome that can evolve to acute myeloid leukemia (AML). Mutations in CSF3R and RUNX1 are frequently observed in CN patients, although how they drive the transition from CN to AML (CN/AML) is unclear. Here we establish a model of stepwise leukemogenesis in CN/AML using CRISPR-Cas9 gene editing of CN patient-derived iPSCs. We identified BAALC upregulation and resultant phosphorylation of MK2a as a key leukemogenic event. BAALC deletion or treatment with CMPD1, a selective inhibitor of MK2a phosphorylation, blocked proliferation and induced differentiation of primary CN/AML blasts and CN/AML iPSC-derived hematopoietic stem and progenitor cells (HSPCs) without affecting healthy donor or CN iPSC-derived HSPCs. Beyond detailing a useful method for future investigation of stepwise leukemogenesis, this study suggests that targeting BAALC and/or MK2a phosphorylation may prevent leukemogenic transformation or eliminate AML blasts in CN/AML and RUNX1 mutant BAALC(hi) de novo AML.

引用

页码：906 / +

页数：23

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