Satomi Tanaka

Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2(flox/flox) mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML. Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia-like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.

3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells.

Recent advances in stem cell biology have identified tumor‐initiating cells (TICs) in a variety of cancers including hepatocellular carcinoma (HCC). Polycomb group gene products such as BMI1 and EZH2 have been characterized as general self‐renewal regulators in a wide range of normal stem cells and TICs. We previously reported that Ezh2 tightly regulates the self‐renewal and differentiation of murine hepatic stem/progenitor cells. However, the role of EZH2 in tumor‐initiating HCC cells remains unclear. In this study, we conducted loss‐of‐function assay of EZH2 using short‐hairpin RNA and pharmacological inhibition of EZH2 by an S‐adenosylhomocysteine hydrolase inhibitor, 3‐deazaneplanocin A (DZNep). Both EZH2‐knockdown and DZNep treatment impaired cell growth and anchorage‐independent sphere formation of HCC cells in culture. Flow cytometric analyses revealed that the two approaches decreased the number of epithelial cell adhesion molecule (EpCAM)+ tumor‐initiating cells. Administration of 5‐fluorouracil (5‐FU) or DZNep suppressed the tumors by implanted HCC cells in non‐obese diabetic/severe combined immunodeficient mice. Of note, however, DZNep but not 5‐FU predominantly reduced the number of EpCAM+ cells and diminished the self‐renewal capability of these cells as judged by sphere formation assays. Our findings reveal that tumor‐initiating HCC cells are highly dependent on EZH2 for their tumorigenic activity. Although further analyses of TICs from primary HCC would be necessary, pharmacological interference with EZH2 might be a promising therapeutic approach to targeting tumor‐initiating HCC cells.

Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.

Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes

Polycomb group gene Bmi1 functions as a tumor suppressor in myelofibrosis.

Direct activation of STAT5 by ETV6-LYN fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis

Myeloproliferative neoplasms (MPN), a group of haematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the fusion of the ETV6 gene to the LYN gene (ETV6‐LYN) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of ETV6‐LYN into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged LYN kinase in the pathogenesis of MPN with myelofibrosis. However, the signalling molecules directly downstream from and activated by ETV6‐LYN remain unknown. In this study, we demonstrated that the direct activation of STAT5 by ETV6‐LYN is crucial for the development of MPN. ETV6‐LYN was constitutively active as a kinase through autophosphorylation. ETV6‐LYN, but not its kinase‐dead mutant, supported cytokine‐free proliferation of haematopoietic cells. STAT5 was activated in a JAK2‐independent manner in ETV6‐LYN‐expressing cells. ETV6‐LYN interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, ETV6‐LYN did not support the formation of colonies by Stat5‐deficient HSCs under cytokine‐free conditions and the capacity of ETV6‐LYN to induce MPN with myelofibrosis was profoundly attenuated in a Stat5‐null background. These findings define STAT5 as a direct target of ETV6‐LYN and unveil the LYN‐STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukaemia.

Posterior reversible encephalopathy syndrome in an adult patient with acute lymphoblastic leukemia after remission induction chemotherapy

Posterior reversible encephalopathy syndrome (PRES) has been reported in childhood leukemia patients increasingly frequently. However, the development of PRES in adult leukemia patients during chemotherapy is very rare. We present a case of PRES in an adult patient with acute lymphoblastic leukemia (ALL) after remission induction chemotherapy. A 28-year-old woman with ALL was administered remission induction chemotherapy consisting of cyclophosphamide, daunorubicin, vincristine, prednisone, and l-asparaginase. After initiation of chemotherapy, the patient developed paralytic ileus and hypertension, and on day 30, she suddenly developed generalized convulsions, loss of visual acuity, and muscle weakness in the legs. Magnetic resonance imaging findings and her signs and symptoms were typical of PRES. The symptoms gradually improved following treatment with an anticonvulsant and an antihypertensive agent, and the patient underwent allogeneic bone marrow transplantation. She has completely recovered from PRES and has been asymptomatic without leukemia relapse. During remission induction chemotherapy for ALL, PRES may be caused by multiple drugs, such as l-asparaginase, vincristine, and corticosteroids, with different mechanisms of action. PRES should be recognized as an important complication, which will occur more frequently with the increased intensity of chemotherapy for adult ALL patients.

Low-dose trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT.

Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT

Successful treatment with rituximab and donor lymphocyte infusions for fulminant EBV-associated lymphoproliferative disorder that developed 14 years after unrelated BMT.

Successful treatment with rituximab and donor lymphocyte infusions for fulminant EBV-associated lymphoproliferative disorder that developed 14 years after unrelated BMT

Illuminant color estimation based on pigmentation separation from human skin color

Human has the visual system called “color constancy” that maintains the perceptive colors of same object across various light sources. The effective method of color constancy algorithm was proposed to use the human facial color in a digital color image, however, this method has wrong estimation results by the difference of individual facial colors. In this paper, we present the novel color constancy algorithm based on skin color analysis. The skin color analysis is the method to separate the skin color into the components of melanin, hemoglobin and shading. We use the stationary property of Japanese facial color, and this property is calculated from the components of melanin and hemoglobin. As a result, we achieve to propose the method to use subject’s facial color in image and not depend on the individual difference among Japanese facial color.