Evolutionary reversion in tumorigenesis.

Cells forming malignant tumors are distinguished from those forming normal tissues based on several features: accelerated/dysregulated cell division, disruption of physiologic apoptosis, maturation/differentiation arrest, loss of polarity, and invasive potential. Among them, accelerated cell division and differentiation arrest make tumor cells similar to stem/progenitor cells, and this is why tumorigenesis is often regarded as developmental reversion. Here, in addition to developmental reversion, we propose another insight into tumorigenesis from a phylogeny viewpoint. Based on the finding that tumor cells also share some features with unicellular organisms, we propose that tumorigenesis can be regarded as "evolutionary reversion". Recent advances in sequencing technologies and the ability to identify gene homologous have made it possible to perform comprehensive cross-species transcriptome comparisons and, in our recent study, we found that leukemic cells resulting from a polycomb dysfunction transcriptionally resemble unicellular organisms. Analyzing tumorigenesis from the viewpoint of phylogeny should reveal new aspects of tumorigenesis in the near future, and contribute to overcoming malignant tumors by developing new therapies.

Tracing the evolutionary history of blood cells to the unicellular ancestor of animals.

Blood cells are thought to have emerged as phagocytes in the common ancestor of animals followed by the appearance of novel blood cell lineages such as thrombocytes, erythrocytes, and lymphocytes, during evolution. However, this speculation is not based on genetic evidence and it is still possible to argue that phagocytes in different species have different origins. It also remains to be clarified how the initial blood cells evolved; whether ancient animals have solely developed de novo programs for phagocytes or they have inherited a key program from ancestral unicellular organisms. Here, we traced the evolutionary history of blood cells, and cross-species comparison of gene expression profiles revealed that phagocytes in various animal species and Capsaspora (C.) owczarzaki, a unicellular organism, are transcriptionally similar to each other. We also found that both phagocytes and C. owczarzaki share a common phagocytic program, and that CEBPα is the sole transcription factor highly expressed in both phagocytes and C. owczarzaki. We further showed that the function of CEBPα to drive phagocyte program in nonphagocytic blood cells has been conserved in tunicate, sponge, and C. owczarzaki. We finally showed that, in murine hematopoiesis, repression of CEBPα to maintain nonphagocytic lineages is commonly achieved by polycomb complexes. These findings indicate that the initial blood cells emerged inheriting a unicellular organism program driven by CEBPα and that the program has also been seamlessly inherited in phagocytes of various animal species throughout evolution.

[The origin of blood cells and myeloid cells].

In human hematopoiesis, cells of various lineages exist, such as neutrophils, lymphocytes, and erythrocytes. Unveiling the pathway from stem cells to the various lineages helps us understand the blood disorders and develop therapies for them. We have studied the developmental pathway of hematopoiesis for decades and found that myeloid potential is retained just before the differentiation into each lineage of the various lineage progenitors. This uniqueness of myeloid cells might reflect the character of mixed-phenotype leukemia and provide a very important clue in determining the evolutional history of blood cells. Recent studies concerning the differentiation pathways of megakaryocytes and granulocytes as well as the findings on the hemocytes of invertebrates have strongly supported the concept of the uniqueness of myeloid cells and enabled us to propose insights into the evolutional history of blood. In this paper, we discuss the origin of blood cells in the context of developmental pathways during ontogeny and phylogeny.

High-dose cytarabine chemotherapy (≥4 g/m2/day) before allogeneic hematopoietic stem cell transplantation for non-core-binding-factor AML in the first complete remission.

Benefit of high-dose cytarabine (HD-AraC) for acute myeloid leukemia (AML) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. We retrospectively analyzed data from 79 non-core-binding-factor AML patients who underwent allo-HSCT in their first complete remission (CR1). In univariate analysis, HD-AraC (≥4 g/m2/day) before allo-HSCT improved disease-free survival (DFS) (p = .018), overall survival (OS) (p = .029), and cumulative incidence of relapse (CIR) (p = .033). Four-year DFS, OS, and CIR of patients receiving and not receiving HD-AraC were 79% vs. 49%, 82% vs. 56%, and 18% vs. 42%, respectively. In multivariate analysis, HD-AraC was a positive prognostic factor for DFS (hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.14-0.88), OS (HR = 0.37, 95% CI: 0.14-0.99), and CIR (HR = 0.38, 95% CI; 0.14-1.0). Our study demonstrates that HD-AraC before allo-HSCT at a dose ≥4 g/m2/day is effective for treating AML patients in CR1.

Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection.

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.

HIV-related NK/T-cell lymphoma in the brain relapsed during intensive chemotherapy but regressed after chemotherapy discontinuation: the importance of maintaining cellular immunity.

This study reports a case of human immunodeficiency virus (HIV)-related natural killer/T-cell lymphoma with an unexpected clinical course. The lymphoma cells were positive for Epstein-Barr virus and the primary nodal lesions regressed after chemotherapy and combined antiretroviral therapy (c-ART); however, brain metastasis progressed along with a reduction in the CD8+ T-cell count. Chemotherapy was discontinued and the patient was treated with c-ART alone, resulting in regression of the brain lesions and recovery of the CD8+ T-cell count. This case highlights the importance of maintaining anti-tumor immunity in patients with HIV-related lymphoma.

The need for continuing chemotherapy for leukemic cell lysis pneumopathy in patients with acute myelomonocytic/monocytic leukemia.

Although fatal pulmonary complications frequently occur during the course of acute leukemia, a minor proportion of the complications are due to leukemia itself. Infections, drug reactions and concomitant medical conditions are the major causes of respiratory distress in leukemic patients. We treated four patients with acute myeloid leukemia complicated by leukemic cell lysis pneumopathy (LCLP). All of the patients had leukemia of monocytoid origin and their respiratory function deteriorated soon after chemotherapy initiation. Although two of the patients required mechanical ventilation, all four improved after continued chemotherapy. Our experience indicates that, in cases of LCLP, chemotherapy should be continued with maximal respiratory support.