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BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells.

BET-inhibition by JQ1 promotes proliferation and self-renewal capacity of hematopoietic stem cells.
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Wroblewski M, Scheller-Wendorff M, Udonta F, Bauer R, Schlichting J, Zhao L, Ben Batalla I, Gensch V, Päsler S, Wu L, Wanior M, Taipaleenmäki H, Bolamperti S, Najafova Z, Pantel K, Bokemeyer C, Qi J, Hesse E, Knapp S, Johnsen S, Loges S,


Wroblewski M, Scheller-Wendorff M, Udonta F, Bauer R, Schlichting J, Zhao L, Ben Batalla I, Gensch V, Päsler S, Wu L, Wanior M, Taipaleenmäki H, Bolamperti S, Najafova Z, Pantel K, Bokemeyer C, Qi J, Hesse E, Knapp S, Johnsen S, Loges S, (click to view)

Wroblewski M, Scheller-Wendorff M, Udonta F, Bauer R, Schlichting J, Zhao L, Ben Batalla I, Gensch V, Päsler S, Wu L, Wanior M, Taipaleenmäki H, Bolamperti S, Najafova Z, Pantel K, Bokemeyer C, Qi J, Hesse E, Knapp S, Johnsen S, Loges S,

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Haematologica 2018 03 22() pii 10.3324/haematol.2017.181354

Abstract

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 outstanding. 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, it 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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