CD47 expression in acute myeloid leukemia varies according to genotype

Abstract

CD47 expression in acute myeloid leukemia varies according to genotypeCD47 is a "don't eat me" signal to phagocytes, that is overexpressed in solid and blood tumors and represents a key mechanism of immune evasion in cancer. 1 Engagement of signal-regulating protein (SIRP) on phagocytic cells by CD47 prevents phagocytosis of tumor cells. 1 In acute myeloid leukemia (AML), CD47 is known to be upregulated on leukemia stem cells (LSC) to avoid phagocytosis 2,3 and increased expression of CD47 commonly predicts worse overall survival. 3CD47-directed blocking monoclonal antibodies are effective against AML engraftment in preclinical models, by inducing phagocytosis of LSC, 3 and several clinical trials are currently evaluating the efficacy of the Hu5F9-G4 monoclonal antibody magrolimab, alone or in combination with other anti-leukemic compounds in adult AML patients.Early results from two phase Ib trials have shown some clinical efficacy of anti-CD47/magrolimab in AML, 4,5 but solid data on the leukemic patients who are more likely to benefit from this immunotherapeutic approach, according to the underlying genotype, is still lacking.Here, we provide a detailed immunohistochemical characterization of CD47 protein expression on leukemic cells from formalin-or B5-fixed paraffin-embedded bone marrow sections across AML genomic spectrum, according to 2022 European-LeukemiaNET (ELN) risk stratification, and complement it with bulk transcriptome analysis of leukemic cells from AML patients included in the Beat-AML dataset. 6e investigated a cohort of adult AML patients (n=53) from University College of London Cancer Center, London, UK, and the Institute of Hematology, University Hospital of Perugia, Italy.Risk stratification was as follows: 19 of 53 (36%) had low-risk, 19 of 53 (36%) intermediate-risk, and 15 of 53 (28%) adverse-risk AML.Low-risk AML included three (16%) cases with RUNX1/RUNX1T1, eight (42%) with CBF/MYH11 and eight (42%) patients with NPM1 mut FLT3 wt AML.The intermediate-risk category included seven (37%) patients with NPM1 mut FLT3-internal tandem dublication (ITD), four (21%) with NPM1 wt FLT3-ITD and eight (42%) with KMT2A/MLLT3rearranged AML.The adverse-risk category included five (33%) patients carrying KMT2A-rearranged AML (other than KMT2A/MLLT3 fusion), three (20%) having chromosome 3 aberrations, four (27%) with monosomy 7, and three (20%) with a complex karyotype.The clinicopathologic features of the study cohort are summarized in Table 1.Immunostaining for CD47 of bone marrow (BM) biopsy specimens from AML patients was performed using the recombinant rabbit monoclonal anti-CD47 antibody, EPR21794 clone (Abcam, ab218810); notably, the anti-CD47 antibody (EPR21794 clone) used in this study, as well as the Hu5F9-G4 monoclonal

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