Page 11 - Haematologica April 2020

Editorials
Figure 1. (A) A single nucleotide polymorphism hampering a binding site for the transcription factor GATA1 may predict whether children with acute lymphoblastic leukemia will need transfusion after chemotherapy. (B) This concept is reflected by the image of a little girl in a hospital thanking her GATA site (mi GATA in Spanish) for not having to undergo transfusion.
megakaryocyte leukemia in children with Down Syndrome and in sporadic forms of acute megakaryocyte leukemia in adults. These mutations are also detected in some patients with the inherited Diamond Blackfan ane- mia. Furthermore, in this disease, hypomorphic levels of GATA1 may result also from mutations in the gene encod- ing the ribosome protein RSP14 that impairs the ribosome ability to bind and translate GATA1 mRNA. In addition, progression of benevolent forms of myeloproliferative neoplasms to their fatal myelofibrosis state is associated with a RSP14 signature that makes megakaryocytes of the patients hypomorphic for GATA1.11 This knowledge has prompted studies that have targeted GATA1 for clinical purposes as pharmacological rescue of GATA1 has been shown to be an effective treatment for myelofibrosis.12 However, surprisingly, GWAS studies have not yet identi- fied clinically relevant correlations between SNP located either in the regulatory regions of GATA1 or in GATA1- DNA binding sites, and variability of erythroid traits. One of the few exceptions is an old study which identified a SNP in the GATA1-binding site of the gene encoding the truncated form of the stem cell kinase receptor that deter- mines the susceptibility to develop polycythemia in response to infection with the Friend virus in mice.13
In this issue of Haematologica, the paper by Xie et al. identifies by whole genome sequencing a single nucleotide polymorphism (SNP) in the intron of a gene (ARHGEF12) encoding a RhoA guanine nucleotide exchange factor which predicts whether children with acute lymphoblastic leukemia (ALL) will require multiple transfusions after chemotherapy.14 On the basis of the assumption that chemotherapy hampers RBC production, and that the requirement for transfusion after this treat- ment depends on the efficiency with which the patient
activates the stress erythropoiesis pathway necessary to overcome anemia, the authors hypothesized that ARHGEF12 encodes a protein that plays an important role in the control of terminal erythroid maturation and that this function is affected by the SNP. To test this hypothe- sis, Xie et al. carefully determined that the SNP is located in a regulatory site disrupting a functional binding site for GATA1 and that, at the homozygous state, it reduces the gene transcription rates by 60%. Loss-of-function studies of ARHGEF12 in animal models indicated that the gene regulates erythropoiesis at the proerythroblast level and studies in cell lines indicated that ARHGEF12 is upstream of a rhoA-p38 signaling pathway, the forced activation of which rescued impaired erythropoiesis induced by ARHGEF12 deficiency in animal models.
This study is important because it provides information on many levels. (1) It identifies a new signaling pathway, ARHGEF12/rhoA/p-38, which regulates the progression of proerythroblasts toward terminal maturation. Although the ligand which activates this pathway has not yet been iden- tified, it is conceivable that it may represent a novel ery- throid-stimulating agent other than erythropoietin which may have clinical value in the treatment of anemia. (2) It identified an SNP which is associated with the requirement for blood transfusion in children with ALL undergoing chemotherapy. If this association is validated by additional prospective studies on children with ALL, and possibly in other cancers, genetic testing for this SNP may represent a biomarker to stratify cancer patients at risk of anemia, allowing the blood supply necessary to support these patients during therapy to be calculated from the data base. (3) Last but not least, it suggests that GWAS studies designed on the basis of well-characterized patient cohorts may be more informative for devising precision/medicine
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