Bahcc1 is critical for the aberrant epigenetic program in a mouse model of MLL-ENL-mediated leukemia.

ABSTRACT: In leukemogenesis, genotoxic stress in hematopoietic stem and progenitor cells (HSPCs) drives individual context-dependent programs of malignant transformation. In light of the various differentiation stages of HSPCs based on a recently revised definition using CD150/CD48, our analyses showed that a subpopulation of long-term repopulating HSCs was most susceptible to MLL-ENL-mediated transformation. An analysis of the molecular mechanism identified Bromo-adjacent homology domain and coiled-coil containing 1 (Bahcc1), which encodes a reader molecule of trimethylated histone H3 lysine 27 (H3K27me3), as a candidate gene involved in distinct susceptibility to leukemic transformation. Interestingly, Bahcc1 was previously reported to be highly expressed in acute myeloid leukemia (AML) with an unfavorable prognosis, including some cases of MLL-rearranged AML. We found that MLL-ENL upregulated Bahcc1 through binding to its promoter, and that Bahcc1 was involved in MLL-ENL-mediated immortalization at least partly through repression of H3K27me3-marked Cdkn1c. Analyses using bone marrow transplantation in mice showed that depletion of Bahcc1 suppressed the leukemogenic activity of MLL-ENL. In a public database, high BAHCC1 expression was found to be associated with a poor prognosis in pediatric AML, in which BAHCC1 expression was significantly lower in MLL-AF9-AML than in other MLL-fusion-AML. These findings shed light on the distinct immortalization potential of HSPCs and suggest a novel MLL-fusion-Bahcc1 axis, which may lead to development of molecular targeted therapy against MLL-fusion-mediated leukemia.

[Successful disease control of plasma cell leukemia by the treatment comprising proteasome inhibitors, followed by daratumumab, lenalidomide, and dexamethasone therapy].

A 59-year-old woman was referred by her family doctor to our hospital owing to anemia, nausea, and malaise. She was diagnosed with primary plasma cell leukemia based on her laboratory and morphologic findings. She was treated with high dose of dexamethasone; cyclophosphamide, bortezomib, and dexamethasone; and carfilzomib, lenalidomide, and dexamethasone. She achieved partial treatment response. We switched her treatment to daratumumab, lenalidomide, and dexamethasone (DRd) owing to progression of peripheral neuropathy. Bone marrow examination performed after 15 courses of DRd revealed minimal residual disease-negative status. Sequential multidrug combination chemotherapies may be related to long-term successful disease control.

Achievement of long-term remission of disseminated histoplasmosis in an AIDS patient.

Histoplasmosis, a fungal infection caused by Histoplasma capsulatum, is poor prognosis once it disseminated, especially in immunocompromised patients. A 50-year-old Japanese-Brazilian male with multiple cervical lymphadenopathies was diagnosed as disseminated histoplasmosis and acquired immunodeficiency syndrome (AIDS). Anti-fungal therapy was initiated followed by anti-retroviral therapy (ART). He achieved long-term remission by treatment with voriconazole. Here we report a case of an AIDS patient with disseminated histoplasmosis who achieved long-term survival in non-endemic area.

Metformin-associated lactic acidosis treated with continuous renal replacement therapy.

Metformin-associated lactic acidosis (MALA) is a rare but life-threatening complication. We report a case of MALA in a man aged 71 years who was treated with continuous renal replacement therapy (CRRT). The patient was brought to the hospital for prolonged and gradual worsening gastrointestinal symptoms. Although he received intravenous treatment, he developed catecholamine-resistant shock, and blood gas analysis revealed lactic acidosis. Bicarbonate and antibiotics for possible sepsis were initiated, but with no clear benefit. Owing to haemodynamic instability with metabolic acidosis, urgent CRRT was given: it was immediately effective in reducing lactate levels; pH values completely normalised within 18 hours, and he was stabilised. MALA sometimes presents with non-specific symptoms, and is important to consider when treating unexplainable metabolic acidosis. In severe cases, CRRT has potential merit, particularly in haemodynamically unstable patients. It is important to be familiar with MALA as a medical emergency, even for emergency physicians.

Plzf drives MLL-fusion-mediated leukemogenesis specifically in long-term hematopoietic stem cells.

Oncogenic transformation requires unlimited self-renewal. Currently, it remains unclear whether a normal capacity for self-renewal is required for acquiring an aberrant self-renewal capacity. Our results in a new conditional transgenic mouse showed that a mixed lineage leukemia (MLL) fusion oncogene, MLL-ENL, at an endogenous-like expression level led to leukemic transformation selectively in a restricted subpopulation of hematopoietic stem cells (HSCs) through upregulation of promyelocytic leukemia zinc finger (Plzf). Interestingly, forced expression of Plzf itself immortalized HSCs and myeloid progenitors in vitro without upregulation of Hoxa9/Meis1, which are well-known targets of MLL fusion proteins, whereas its mutant lacking the BTB/POZ domain did not. In contrast, depletion of Plzf suppressed the MLL-fusion-induced leukemic transformation of HSCs in vitro and in vivo. Gene expression analyses of human clinical samples showed that a subtype of PLZF-high MLL-rearranged myeloid leukemia cells was closely associated with the gene expression signature of HSCs. These findings suggested that MLL fusion protein enhances the self-renewal potential of normal HSCs to develop leukemia, in part through a Plzf-driven self-renewal program.