Multiple myeloma hinders erythropoiesis and causes anaemia owing to high levels of CCL3 in the bone marrow microenvironment

Abstract

Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

“…Thus, the potential of erythroid differentiation of HSCs is commonly suppressed, especially in the bone marrow. EPC precursors, MEPs, are the most suppressed progenitor cells in the bone marrow of mice with hematological malignancies [ 57 , 58 , 136 , 140 , 152 , 153 , 154 ]. In plasma cell myeloma, malignant cell infiltration correlates negatively with hemoglobin concentration, but not with leukocytes or platelet counts, which suggests the selective impairment of erythropoiesis by malignant cells [ 155 ].…”

“…TGF-β induces the maturation arrest of early-stage EPCs by noncanonical activation of p38, which in turn triggers GATA1 degradation [ 57 , 58 , 140 ]. Moreover, TGF-β activates SMAD2 and SMAD3 via the type III TGF-β receptor, which is transiently upregulated in early-stage EPCs [ 178 ].…”

“…Erythropoiesis is also influenced by dysregulated chemokine profiles in the bone marrow plasma and serum of cancer patients. One of these chemokines is CCL3, which is upregulated in the majority of patients with hematopoietic malignancies [ 57 , 58 ] and a subset of patients with solid tumors [ 225 ]. CCL3 suppresses erythroid differentiation by p38 activation via CCR1, and this leads to the degradation of GATA1 [ 57 , 58 , 226 ].…”

“…One of these chemokines is CCL3, which is upregulated in the majority of patients with hematopoietic malignancies [ 57 , 58 ] and a subset of patients with solid tumors [ 225 ]. CCL3 suppresses erythroid differentiation by p38 activation via CCR1, and this leads to the degradation of GATA1 [ 57 , 58 , 226 ]. On the other side, chemokines may also promote erythropoiesis by recruiting monocyte-derived macrophages to create erythroblastic islands in the extramedullary sites [ 227 ].…”

Potent but transient immunosuppression of T-cells is a general feature of CD71+erythroid cells

“…ROS also may decrease CD3ζ in T-cells 29 We further demonstrated that EPCs expand in anemic patients and suppress T-cells. Anemia correlates with worse outcomes in many diseases, including pneumonia 30 or cancer 31 . Moreover, preoperative anemia is associated with an increased risk of infection and mortality in patients undergoing surgery 32, .…”