To determine the significance of increased Wilms tumor 1 (WT1) gene expression in the peripheral blood of patients with acquired aplastic anemia (AA), we analyzed serial changes in WT1 mRNA copy number (WT1cn) in 63 patients with AA as well as in five patients with myelodysplastic syndromes (MDS) and seven patients with paroxysmal nocturnal hemoglobinuria (PNH). WT1cn was higher than the cut-off (≥50 copies/μg RNA) at the time of the first measurement in 41% of untreated (60–190 copies/μg RNA [median 130]) and 59% of treated (59–520 copies/μg RNA [median 150]) AA patients. Although WT1cns gradually increased in most AA patients during the 2–105 months follow-up period, they did not lead to clonal evolution except in three patients in whom the maximum change ratio of WT1cn (WT1cn-change max), defined as the ratio of WT1cn at the first examination to that of the maximum value, exceeded 20.0 and who developed MDS at 2, 46, and 105 months. Increased WT1 gene expression was enriched in granulocytes rather than in mononuclear cells in most WT1-positive AA patients and did not correlate with mutations of genes associated with myeloid malignancy. WT1cns were high at 690–5700 (median 2000) in MDS patients and remained high thereafter, while WT1cns in PNH patients (77–200; median 96) were similar to those in AA. Thus, moderate increases in WT1cns up to 600 are common in AA patients in stable remission. An increase in the WT1cn-change max over 20.0 may portend transformation from AA to MDS.

A 64-year-old man with angioimmunoblastic T-cell lymphoma (AITL) subsequently developed diffuse large B-cell lymphoma (DLBCL) and myelodysplastic syndrome (MDS). Genomic profiling of AITL, DLBCL, and MDS samples revealed that the tumor cells from all samples shared common mutations in TET2 and DNMT3A . In addition, the IDH2 mutation was observed in AITL, and TP53 mutation was observed in DLBCL and MDS. These findings illustrate the clonal relationship between AITL and DLBCL in addition to AITL and MDS, with the latter being increasingly reported. The present findings strongly support the theory of multistep and multilineage tumorigenesis from a common founder clone.

In a cohort of 3131 patients with myeloproliferative neoplasms (MPNs), we identified 200 patients (6.4%) who reported a second case of haematological malignancies (HM) in first- or second-degree relatives. The occurrence of a second HM in the family was not influenced by MPN subtype, sex or driver mutation, while it was associated with age at MPN diagnosis: 8.5% of patients diagnosed with MPN younger than 45 years had a second relative affected with HM compared to 5.5% of those diagnosed at the age of 45 years or older ( p =  0.003), thus suggesting a genetic predisposition to HM with early onset.

The phenotypic changes in hematopoietic stem progenitor cells (HSPCs) with somatic mutations of malignancy-related genes in patients with acquired aplastic anemia (AA) are poorly understood. As our initial study showed increased CXCR4 expression on HLA allele-lacking (HLA[−]) HSPCs that solely support hematopoiesis in comparison to redundant HLA(+) HSPCs in AA patients, we screened the HSPCs of patients with various types of bone marrow (BM) failure to investigate their CXCR4 expression. In comparison to healthy individuals ( n  = 15, 12.3%–49.9%, median 43.2%), the median CXCR4 + cell percentages in the HSPCs of patients without somatic mutations were low: 29.3% (14.3%–37.3%) in the eight patients without HLA(−) granulocytes, 8.8% (4.1%–9.8%) in the five patients with HLA(−) cells accounting for >90% of granulocytes, and 7.8 (2.1%–8.7%) in the six patients with paroxysmal nocturnal hemoglobinuria. In contrast, the median percentage was much higher (78% [61.4%–88.7%]) in the five AA patients without HLA(−) granulocytes possessing somatic mutations ( c-kit , t[8;21], monosomy 7 [one for each], ASXL1 [ n  = 2]), findings that were comparable to those (66.5%, 63.1%–88.9%) in the four patients with advanced myelodysplastic syndromes. The increased expression of CXCR4 may therefore reflect intrinsic abnormalities of HSPCs caused by somatic mutations that allow them to evade restriction by BM stromal cells.

Diamond-Blackfan anaemia (DBA) shares clinical features with two recently reported sporadic cases of dyserythropoietic anaemia with a cryptic GATA1 splicing mutation (c.871-24 C>T). We hypothesized that some patients clinically diagnosed with DBA but whose causative genes were unknown may carry the intronic GATA1 mutation. Here, we examined 79 patients in our DBA cohort, who had no detectable causative genes. The intronic GATA1 mutation was identified in two male patients sharing the same pedigree that included multiple cases with anaemia. Cosegregation of this mutation and disease in multiple family members provide evidence to support the pathogenicity of the intronic GATA1 mutation.