Lanying Zhao

Azacitidine is a mainstay of therapy for myelodysplastic syndrome (MDS)–related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their posttreatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pretreatment (n = 449) and posttreatment (n = 289) bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their posttreatment clone size on treatment outcomes. In Cox proportional hazard modeling, multihit TP53 mutation (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.42-2.91; P < .001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P = .009), and DDX41 mutation (HR, 0.33; 95% CI, 0.17-0.62; P < .001), together with age, high-risk karyotypes, low platelets, and high blast counts, independently predicted OS. Posttreatment clone size accounting for all drivers significantly correlated with International Working Group (IWG) response (P < .001, using trend test), except for that of DDX41-mutated clones, which did not predict IWG response. Combined, IWG response and posttreatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, the molecular International Prognostic Scoring System (IPSS-M; c-index, 0.653 vs 0.688; P < .001, using likelihood ratio test). In conclusion, evaluation of posttreatment clone size, together with the pretreatment mutational profile as well as the IWG response play a role in better prognostication of azacitidine-treated patients with myelodysplasia.

Supplementary Table from Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

Supplementary Figure from Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

Supplementary Figure from Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL.Significance:This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions.This article is highlighted in the In This Issue feature, p. 369

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL.Significance:This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions.This article is highlighted in the In This Issue feature, p. 369

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. Significance: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369

The complete mitochondrial genome for Gymnocypris eckloni and Gymnocypris przewalskii ganzihonensis is 16,686 and 16,682 bp in size, respectively. Both of the mitochondrial genomes have identical genomic organization and structure including 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes and 1 control region as found in other vertebrates, with the exception of 86 bp non-coding nucleotides between tRNA^Thr and tRNA^Pro. The phylogenetic analyses based on the concatenated nucleotide sequence of 12 PCGs on the heavy strand supported a relatively closed relationship among G. eckloni, G. p. przewalskii and G. p. ganzihonensis. The sequence divergence between G. eckloni and G. przewalskii, as well as within G. przewalskii, is relatively low compared to the average sequence divergence among other cyprinid fishes, suggesting that they are the most closely related species resulted from a relatively recent speciation event. The estimated molecular divergence time is coincided with a relatively recent speciation event occurring during the separation of the Yellow River and Qinghai Lake.