-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1346 Multiple Myeloma Cell Defects Erythropoiesis and Results Anemia Via High Level of CCL3 in Bone Marrow Microenvironment

Program: Oral and Poster Abstracts
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster I
Hematology Disease Topics & Pathways:
Anemias, Diseases, Biological Processes, erythropoiesis, microenvironment
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Lanting Liu1*, Zhen Yu, MD2*, Hui Cheng2*, Weiwei Sui3*, Shuhui Deng, MD3*, Xiaojing Wei2*, Chenxing Du, MD4*, Wenyang Huang3*, Gang An5*, Wen Zhou, PhD6, Tao Cheng7, Lugui Qiu, MD2 and Mu Hao4*

1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiajin, China
2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
3National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Blood Diseases Hospital & Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, TIANJIN, China
5lymphoma and myeloma center, National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Blood Diseases Hospital & Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
6Cancer Research Institute, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education; Key Laboratory of Carcinogenesis, National Health and Family Planning Commission, Central South University, Changsha, Hunan, China
7State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China

Background: Anemia is the most common complication of myeloma, and is associated with worse clinical outcomes including diminished quality of life, and increased risk of morbidity and mortality. Bone marrow (BM) is the main location of the growth and differentiation of HSPCs. Although marrow replacement by myeloma cell is widely considered a mechanistic rationale for myeloma-related anemia, however the molecular mechanism has not been fully understood.

Methods: The clinical characteristics and the prognostic impact of myeloma-related anemia were investigated in patients with multiple myeloma. The erythroid differentiation defects of HSPCs were examined by flow cytometry and colony-formation assay. RNA-seq were conducted to clarify the different gene expression and the signaling pathway in HSPCs. Relative protein levels were determined by immunoblotting and relative gene levels were determined by quantitative real-time PCR. 5TGM1 murine myeloma mouse model was utilized.

Results: The data of our large cohort of 1,363 myeloma patients demonstrated that 84.4% of patients had anemia (Hgb<120 g/L), more than 50% of patients had moderate (Hgb=90-120 g/L) or severe anemia (Hgb=60-90 g/L) at the time of diagnosis. Anemia positively correlated with myeloma cell infiltration in the BM and worse outcome of patient. Patient sample and mouse model indicated that the quantity and the erythroid differentiation of HSPCs were affected by myeloma cell infiltration. The number of HPCs was significantly declined in the BM of myeloma, and negatively correlated with the quantity of tumor cells. The master regulator of erythropoiesis GATA1 and KLF1, was obviously down-regulated in myeloma HSPCs cells. However, the gene of chemokine CCL3 was significantly upregulated. Elevated CCL3 in the BM plasma of myeloma further inhibited erythropoiesis of HSPCs through activation of CCL3/CCR1/p38 signaling, and suppressed the expression of GATA1. CCR1 antagonist treatment effectively inhibits CCL3 activity and recovered the expression of GATA1 and rescued the erythropoiesis of HSPCs.

Conclusions: myeloma cell infiltration causes the elevation of CCL3 in microenvironment that suppresses the erythropoiesis of HSPCs and results in anemia by downregulating the level of GATA1 of HSPCs. Thus, our study indicates targeting CCL3 would be a potential strategy against anemia and improvement the survival of myeloma patient.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH