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ARHGEF12 in erythropoiesis of chemotherapy patients
(MRT) and 31 patients with no RBC transfusion (NRT), all from the SCMC-ALL-2005 cohort (Figure 1A). Considering the variations in patient age and body weight, the RBC transfusion amount was normalized by patient body surface area taking into account only post- remission transfusions in order to minimize the effect of ALL itself. By a GWAS analysis, 1,708 SNPs of 281 genes passed the criterion of the primary cut: a call rate of >95% and P<0.01. Of interest, most of the SNPs were located in introns adjacent to exons, suggesting that these polymor- phisms are relevant to chemotherapy-induced anemia by regulating gene expression. These genes could be highly expressed in hematopoietic cells and involved in erythroid differentiation from hematopoietic stem/progenitor cells.
To address this possibility, we sorted the primary gene list with expression patterns in primitive CD34+ cells before erythroid differentiation and in erythrocytes based on the Differentiation Map Portal (DMAP) database.3 A total of 35 genes were enriched by this analysis. Among them, 12 genes were highly expressed in hematopoietic stem/prog- enitor cells (HSPC) and 23 genes were expressed in ery- throcytes with over two times the average expressions. At the top of this enriched list were GUCY1A3,4 NUCB2, TFDP2,5 CHPT1,6 PLCB1,7 LPIN2,8 TNS1,9,10 BSG,11,12 COL5A1,13 ANXA7,14 EPB42,15,16 RAP1GAP,17 ARHGEF12,10,18 ABCC419 and FARP120 (Tables 2 and 3 and Figure 1B). Interestingly, most of these genes are well- known in association with erythropoiesis or cytotoxicity
A
B
Figure 1. Genomic characterizations of chemotherapy-induced anemia in children with acute lymphoblastic leukemia (ALL). (A). The schematic treatment plan of SCMC-ALL 2005. LR: low-risk group; MR: medium-risk group; HR: high-risk group; P: prednisone window phase; Is: induction for standard-risk patients; Ih: induction for higher risk patients; Cs: consolidation for standard patients; Ch: consolidation for higher risk patients; M: high-dose methotrexate; Rs: re-induction for standard- risk patients; Rh: re-induction for higher risk patients; Mt: maintenance therapy; CAT HAD: chemotherapy course composed of cyclophosphamide, cytarabine, thiop- urine and high-dose cytarabine. (B). An outline of the genomic characterizations. Genome-wide association study (GWAS) was performed based on whole exome sequencing data for 31 cases in each cohort of multiple red blood cell transfusion (MRT, >8 units/m2) and no red blood cell transfusion (NRT). 23 genes highly expressed in erythoid committed and 12 genes highly expressed in pre-erythroid committed were on the list of genes with significance (call rate >95% and P<0.01).
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