TY - JOUR
T1 - BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells
AU - Wroblewski, Mark
AU - Scheller-Wendorff, Marina
AU - Udonta, Florian
AU - Bauer, Raimund
AU - Schlichting, Jara
AU - Zhao, Lin
AU - Batalla, Isabel Ben
AU - Gensch, Victoria
AU - Päsler, Sarina
AU - Wu, Lei
AU - Wanior, Marek
AU - Taipaleenmäki, Hanna
AU - Bolamperti, Simona
AU - Najafova, Zeynab
AU - Pantel, Klaus
AU - Bokemeyer, Carsten
AU - Qi, Jun
AU - Hesse, Eric
AU - Knapp, Stefan
AU - Johnsen, Steven
AU - Loges, Sonja
N1 - Publisher Copyright:
© 2018 Ferrata Storti Foundation.
PY - 2018/6/3
Y1 - 2018/6/3
N2 - Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, JQ1 treatment increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen. Furthermore, JQ1 induces proliferation of long-term hematopoietic stem cells, thereby increasing stem cell numbers. Due to increased numbers, JQ1-treated hematopoietic stem cells engrafted better after stem cell transplantation and repopulated the hematopoietic system significantly faster after sublethal myeloablation. As quantity and functionality of hematopoietic stem cells determine the duration of life-threatening myelosuppression, BET inhibition might benefit patients in myelosuppressive conditions.
AB - Although inhibitors of bromodomain and extra terminal domain (BET) proteins show promising clinical activity in different hematologic malignancies, a systematic analysis of the consequences of pharmacological BET inhibition on healthy hematopoietic (stem) cells is urgently needed. We found that JQ1 treatment decreases the numbers of pre-, immature and mature B cells while numbers of early pro-B cells remain constant. In addition, JQ1 treatment increases apoptosis in T cells, all together leading to reduced cellularity in thymus, bone marrow and spleen. Furthermore, JQ1 induces proliferation of long-term hematopoietic stem cells, thereby increasing stem cell numbers. Due to increased numbers, JQ1-treated hematopoietic stem cells engrafted better after stem cell transplantation and repopulated the hematopoietic system significantly faster after sublethal myeloablation. As quantity and functionality of hematopoietic stem cells determine the duration of life-threatening myelosuppression, BET inhibition might benefit patients in myelosuppressive conditions.
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U2 - 10.3324/haematol.2017.181354
DO - 10.3324/haematol.2017.181354
M3 - Article
C2 - 29567778
AN - SCOPUS:85048056367
SN - 0390-6078
VL - 103
SP - 939
EP - 948
JO - Haematologica
JF - Haematologica
IS - 6
ER -