Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition

Area of Science:

• Oncology
• Hematology
• Cell Biology

Background:

• Aberrant mammalian target of rapamycin (mTOR) signaling drives various human cancers.
• mTOR pathway inhibitors are promising cancer therapeutics, with dual mTORC1/2 inhibitors like AZD8055 in clinical trials.
• Bone marrow suppression is a common side effect of chemotherapy, but the impact of dual mTORC1/2 inhibition on hematopoietic stem and progenitor cells (HSPCs) remains unclear.

Purpose of the Study:

• To investigate the effects of dual mTORC1/2 inhibition on mouse bone marrow HSPC function and plasticity.
• To determine if pharmacological inhibition of mTORC1/2 impacts the viability and clonogenic potential of hematopoietic cells.

Main Methods:

• Treatment of mouse bone marrow Lin(-)Sca-1(+)c-Kit(+) cells with dual mTORC1/2 inhibitors (AZD8055, KU-63794).
• Assessment of apoptotic cell death and colony-forming unit (CFU) assays to evaluate hematopoietic progenitor cell (HPC) function.
• Analysis of day-14 and day-35 cobblestone area-forming cells (CAFCs) as surrogates for HPCs and HSCs, respectively.

Main Results:

• Dual mTORC1/2 inhibition by AZD8055 or KU-63794 induced apoptotic cell death in mouse BM Lin(-)Sca-1(+)c-Kit(+) cells.
• Inhibition of mTORC1/2 dose-dependently suppressed the clonogenic function of HPCs.
• Dual mTORC1/2 inhibition markedly inhibited day-14 CAFC growth but enhanced day-35 CAFC generation.

Conclusions:

• Dual mTORC1/2 inhibition has distinct effects on hematopoietic progenitor cells (HPCs) versus hematopoietic stem cells (HSCs).
• While HPC function is suppressed, HSC generation may be enhanced, indicating a complex impact on bone marrow hematopoiesis.
• These findings are crucial for understanding and mitigating potential side effects of dual mTORC1/2 inhibitors in cancer therapy.