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ERYTHROFERRONE EXPRESSION LEVELS IN MYELODYSPLATIC SYNDROMES SHOW CLINICAL RELEVANCE

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27 July 2021

AperTO - Archivio Istituzionale Open Access dell'Università di Torino

Original Citation:

ERYTHROFERRONE EXPRESSION LEVELS IN MYELODYSPLATIC SYNDROMES SHOW CLINICAL RELEVANCE

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DOI:10.1002/ajh.24812

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ERYTHROFERRONE EXPRESSION LEVELS IN MYELODYSPLATIC SYNDROMES SHOW

CLINICAL RELEVANCE

Augusta Di Savino, Arianna Savi, Student, Daniela Gallo, MD, Valentina Gaidano, MD, Patrizia

Scaravaglio, PhD, Mauro Mezzabotta, MD, Giuseppe Saglio, MD, PhD, Daniela Cilloni, MD, PhD and De

Gobbi Marco, MD, PhD

Department of Clinical and Biological Sciences

Introduction. Dysregulation of hepcidin, a key iron regulating hormone, is important in the pathogenesis of

iron overload in patients with myelodysplatic syndromes (MDS), heterogeneous clonal myeloid disorders

characterized by ineffective hematopoiesis, especially erythropoiesis, cytopenia and deregulated iron

homeostasis. Recently, Erythroferrone (ERFE) was discovered as a new erythroid-regulator of hepcidin in

the context of erythropoietic stress. ERFE, encoded in humans by the FAM132B gene, induces increased

iron availability by downregulation of hepcidin in the liver and therefore represents an important new factor

in iron homeostasis to be explored as a potential diagnostic or therapeutic target in the context of anemia

and iron overload. In order to determine the specific role of ERFE in MDS, we analyzed the gene

expression of FAM132B in MDS patients and controls and correlated the differential expression data with

clinical parameters and expression level of others iron genes.

Methods. Bone marrow samples from 65 newly diagnosed MDS and 8 non-malignant hematological

patients were collected. The diagnosis of MDS was based on the 2008 World Health Organization (WHO)

classification. Total RNA was extracted with Trizol reagent. Reverse transcription and PCR amplification

were performed according to manufacturer’s instruction. The expression level of each gene was normalized

to the housekeeping gene ABL1 and analyzed by 2-

ΔΔCT

relative quantitative method. Statistical analyses

were performed using GraphPad 4.0 software. P-values of <0.05 were considered statistically significant.

Unpaired t-test or Mann Whitney test was used to study difference between two groups. Correlation

analysis was performed using the Spearman’s rank correlation coefficient r

s

.

Results. We first evaluated the expression of FAM132B in total bone marrow (BM) cells of 65 newly

diagnosed MDS patients. FAM132B expression had a more variable expression pattern in MDS than

controls and was highly expressed in 31 out of 65 patients. In BM cells, expression levels of FAM132B

correlated inversely with those of HAMP and positively with those of FPN1 and EPOR. We next evaluated

FAM132B expression in the different subgroups of WHO classification. ERFE expression was significantly

higher in RA (p=0.0013) and 1 (p=0.001) subtypes when compared with controls, but not in

RAEB-2 or in RCMD. To investigate the potential role of ERFE in a clinical setting, we next conducted

Spearman’s correlation analysis on the mRNA expression of FAM132B and laboratory parameters. Our

results showed that FAM132B was positively correlated with serum iron, ferritin, bone marrow

erythroblasts and MCV and inversely correlated with peripheral RBC.

Discussion and Conclusion. This study analyzes the FAM132B expression in MDS, clonal conditions of the

bone marrow with impaired hematopoiesis, especially erythropoiesis. The observed high overexpression of

FAM132B in MDS patients, its positive correlation with BM erythroblasts but its negative correlation with

peripheral RBC might be related to an abnormal and ineffective erythropoiesis. Moreover, the inverse

correlation between FAM132B and BM HAMP confirms that ERFE is able to modulate, through hepcidin

suppression, the iron homeostasis, not only at systemic level as shown by the correlation with the

laboratory markers of iron metabolism, but also at the BM level. These finding suggest that ERFE may play

an important role in the physiopathology of the dysfunctional erythropoiesis and it could be assessed as

new biomarker in MDS.

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