CALR and CD47: An Insight into Their Roles in the Disease Progression of MDS and MPN

Abstract

Myelodysplastic syndrome and myeloproliferative neoplasms are clonal myeloid disorders arising from haematopoietic stem cells that have the tendency to progress into acute myeloid leukaemia. Multiple prognostic scoring systems have been proposed and utilised in clinical practice to predict disease evolution, however none of them can predict treatment response. In solid tumours, the relationship between the pro-phagocytic calreticulin and the anti-phagocytic CD47 is repeatedly investigated. Overexpression of calreticulin has been documented to produce a pro-phagocytic signal in solid tumour and it is often counteracted by a concomitant expression of the antiphagocytic CD47 as they act in response to one another, reflecting an apoptosis vs survival mechanism in response to chemotherapy. The role of both calreticulin and CD47 are currently poorly understood in myeloid malignancies including myelodysplastic syndrome and myeloproliferative neoplasms. The aim of this review is to elaborate on the current understanding round the roles and implications of calreticulin and CD47 signalling with in solid and haematological cancers, discuss potential roles for calreticulin and CD47 expression in transformation of myeloid cells in patients with MDS or MPN into AML and how these advances are starting to be used to design new therapeutic strategies to determine disease progression and treatment response in both solid cancer and myeloid malignancies.

Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…In preclinical studies, azacitidine was found to simultaneously upregulate cell surface expression of both CD47 and calreticulin in AML and MDS cell lines [ 72 , 73 ]. In vitro, azacitidine plus magrolimab synergistically increased macrophage-mediated phagocytosis of AML cells which translated into a significant improvement in the long-term survival of AML xenograft mouse models [ 71 ].…”

How I Treat TP53-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…AZA has been shown to both increase expression of CD47 and the pro-phagocytic signal calreticulin in myeloid malignancies. AZA synergizes with MAGRO by inducing “eat me” signals on AML, to enhance phagocytosis [ 58 ].…”

Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia

“…For anti-tumor activity, another co-stimulatory signal is needed. Tumor cells may need to express additional pro-phagocytic signals such as SLAMF7 with Mac-1 [ 92 ] and calreticulin induced by azacitidine, [ 93 ] or additional activation of macrophages via Fcγ receptor activation by the Fc region of a monoclonal antibody targeting CD47 or by a second agent targeting leukemia cells (e.g., CD33). Preclinical findings have also shown that F(ab’)2 fragments of a monoclonal antibody against CD47 showed no apoptotic effect on CD34+ hematopoietic progenitor/stem or human endothelial cells in leukemia xenograft mouse models [ 94 ].…”