Chemotherapy-related anemia is regulated through caspase-1-mediated ROCK1 activation

Hematopoietic stem cells (HSCs) have the ability to produce all cells in the blood system and are crucial for blood and immune recovery after chemotherapy. Patients with cancer often experience anemia, especially during chemotherapy treatment. Severe anemia may cause treatment disruption and is closely linked to a worse prognosis for the patient. We followed hematopoietic recovery in mice after chemotherapy treatment with 5-fluorouracil (5-FU) and found that erythrocyte recovery is delayed compared to other blood lineages. The delayed erythroid recovery manifests itself in HSCs that are transcriptionally and functionally biased toward myeloid cell production at the expense of erythropoiesis. We show that this erythroid deficiency is rescued in a caspase-1-/- mouse model, and that caspase-1 regulates lineage bias through an interleukin-1β-independent mechanism involving rho-associated coiled-coil-containing protein kinase 1 (ROCK1). Inhibiting the caspase-1 substrate ROCK1 leads to a rescue of erythropoiesis after 5-FU treatment. Indeed, we confirmed that ROCK1 is cleaved and activated by caspase-1 upon 5-FU treatment, suppressing erythropoiesis. Currently, patients with cancer who are anemic have limited treatment options for improving their red blood cell numbers. Several ROCK1 inhibitors have already been approved for use in other conditions and could potentially be used to mitigate anemia associated with cancer and chemotherapy, thereby improving quality of life and outcomes for patients with cancer.