Saori Katayama

Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

Significance Sickle cell disease (SCD) is one of the most common inherited disorders. A mutation in the β-globin gene causes deformation of red blood cells into a sickle shape, which in turn causes intravascular hemolysis and vaso-occlusion resulting in damage to multiple organs. Most studies that propose to develop new SCD therapies include the induction of fetal γ-globin expression to inhibit sickle cell formation as their ultimate goal. In contrast, we demonstrate here that activation of nuclear factor erythroid 2-related factor 2 (Nrf2) ameliorates the development of inflammation and tissue damage that strongly affect the morbidity of SCD patients. Notably, several compounds that serve as Nrf2 inducers have been developed or are under development. The data indicate that Nrf2 activation could improve the prognosis for SCD patients. Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

Lower Back Pain as a Symptom of Migrainous Corpalgia

The symptoms and prevalence of migraine headaches are widely recognized; however, less is known about migraine-related spontaneous body pain, or migrainous corpalgia. Only a few reports have described it. The case of a 13-year-old boy with onset of migrainous corpalgia at the age of 12 years is presented. He suffered from pulsatile headaches and bilateral lower back pain, which would appear either with the headache or as an isolated symptom. Various medical examinations showed no abnormalities. He was diagnosed as having migraine without aura and successfully treated with valproic acid. It is unique for this patient to have lower back pain as a symptom of migrainous corpalgia. It would be important for physicians to understand the variety of pain symptoms in migraine patients, as shown here, for better and comprehensive understanding of migraine and its related condition.

Another case of lower back pain associated with migraine: the importance of specific questions.

Recently, the authors reported that lower back pain could be a symptom of migrainous corpalgia. Here, they report another pediatric patient who had lower back pain during a migraine, and based on their experience, they stress the importance of specifically asking questions to investigate this curious symptom. A 13-year-old boy visited an outpatient clinic complaining of headaches since the age of 12 years. These initially occurred twice monthly and had increased to 2 to 4 per week at the time of the visit. Headaches lasted 2 to 14 hours during each attack. Headaches were pulsatile or a heavy feeling, very intense, and lateralized to the left. He had occasional nausea, vomiting, and photophobia in conjunction with the headache as well as photopsias and scotoma. Detailed questioning also revealed that he had a painful feeling in his right arm and lower back pain during the attack, although he did not realize they were related to the headache. The neurological examination result between attacks was unremarkable. The blood examination findings were within normal limits, and computed tomography showed no obvious abnormality explaining his headaches. His profile was concordant with migraine with aura based on the criteria of the International Classification of Headache Disorder II. His headaches ameliorated dramatically with the administration of valproic acid. The experience provided confirmative evidence that lower back pain can be a symptom of migrainous corpalgia and highlighted the importance of specific questions by the physician to clarify the existence of hidden symptoms, such as lower back pain. The patient did not realize that his lower back pain was a part of his migraine before the doctors specifically asked about it. The authors speculate that the spatial distance between the head and lower back was related to his lack of awareness. In this context, it is extremely important for physicians to inquire about various symptoms to identify hidden symptoms, especially those whose connection to migraine is not recognized by the patient. Furthermore, such efforts can allow physicians to identify symptoms that are not known to be related on first consideration, as in this case. The authors believe that this recent short report gives physicians brand-new knowledge .

Mesenchymal chondrosarcoma diagnosed on FISH for HEY1‐NCOA2 fusion gene

Mesenchymal chondrosarcoma (MC) is an extremely rare subtype of chondrosarcoma that has a small round‐cell sarcoma with focal cartilaginous differentiation, often with a pericytomatous vascular pattern. The non‐cartilaginous components are usually dominant, and such lesions might be confused with other small round‐cell tumors. Recently, a tumor‐specific HEY1‐NCOA2 fusion gene was identified in MC. Here we report the case of a 9‐year‐old boy who was diagnosed with MC by detection of HEY1‐NCOA2 fusion signals in almost 50% of tumor cells in tissue sections on fluorescence in situ hybridization (FISH). In this way, the tumor was definitively diagnosed as MC. This case suggests that the detection of the HEY1‐NCOA2 fusion gene on FISH is of diagnostic value for MC.

A case series of CAEBV of children and young adults treated with reduced‐intensity conditioning and allogeneic bone marrow transplantation: a single‐center study

Epstein–Barr virus (EBV)‐infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial.

Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis

ABSTRACT GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.

GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis

Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of the EVI1 gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the EVI1 gene reciprocally deprives this enhancer of 1 of the 2 GATA2 alleles, resulting in a loss-of-function genetic reduction in GATA2 abundance. Because GATA2 haploinsufficiency is strongly associated with MDS and AML, we asked whether EVI1 misexpression and GATA2 haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven EVI1 misexpression, but in this case, it was coupled to a Gata2 heterozygous germ line deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemic transformation, resulting in early onset of leukemia. The 3q21q26 mice suffered from leukemia in which B220+ cells and/or Gr1+ leukemic cells occupied their bone marrows. We found that the B220+Gr1-c-Kit+ population contained leukemia-initiating cells and supplied Gr1+ leukemia cells in the 3q21q26 leukemia. When Gata2 expression levels in the B220+Gr1-c-Kit+ cells were decreased as a result of Gata2 heterozygous deletion or spontaneous phenomenon, myeloid differentiation of the B220+Gr1-c-Kit+ cells was suppressed, and the cells acquired induced proliferation as well as B-lymphoid-primed characteristics. Competitive transplantation analysis revealed that Gata2 heterozygous deletion confers selective advantage to EVI1-expressing leukemia cell expansion in recipient mice. These results demonstrate that both the inappropriate stimulation of EVI1 and the loss of 1 allele equivalent of Gata2 expression contribute to the acceleration of leukemogenesis.