Chemotherapy-related anaemia is regulated through Caspase-1 mediated ROCK1 activation

Haematopoietic stem cells have the ability to produce all cells in the blood system and are crucial for blood and immune recovery after chemotherapy. Cancer patients often experience anaemia, especially during chemotherapy treatment. Severe anaemia may cause treatment disruption and is closely linked to a worse prognosis for the patient. We followed haematopoietic recovery in mice after chemotherapy treatment with 5-fluorouracil and found that erythrocyte recovery is delayed compared to other blood lineages. The delayed erythroid recovery manifests itself in haematopoietic stem cells that are transcriptionally and functionally biased towards 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 IL-1β-independent mechanism involving ROCK1. Inhibiting the Caspase-1 substrate ROCK1 leads to a rescue of erythropoiesis after 5-FU. Indeed, we confirmed that ROCK1 is cleaved and activated by Caspase-1 upon 5-FU treatment, suppressing erythropoiesis. Currently, anaemic cancer patients have limited treatment options for improving their red blood cell numbers. Several ROCK1 inhibitors are already approved for use in other conditions and could potentially be utilised for mitigating anaemia during cancer and chemotherapy, improving quality of life and outcomes for cancer patients.