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A number of studies have demonstrated that it is possible to directly convert one cell type to another by factor-mediated transdifferentiation, but in the vast majority of cases, the resulting reprogrammed cells are unable to maintain their new cell identity for prolonged culture times and have a phenotype only partially similar to their endogenous counterparts. To better understand this phenomenon, we developed an analytical approach for better characterizing trans-differentiation-associated changes in DNA methylation, a major determinant of long-term cell identity. By examining various models of transdifferentiation both in vitro and in vivo, our studies indicate that despite convincing expression changes, transdifferentiated cells seem unable to alter their original developmentally mandated methylation patterns. We propose that this blockage is due to basic developmental limitations built into the regulatory sequences that govern epigenetic programming of cell identity. These results shed light on the molecular rules necessary to achieve complete somatic cell reprogramming., Competing Interests: Competing interests statement:The authors declare no competing interest.

In recent years, the pursuit of inducing the trophoblast stem cell (TSC) state has gained prominence as a compelling research objective, illuminating the establishment of the trophoblast lineage and unlocking insights into early embryogenesis. In this review, we examine how advancements in diverse technologies, including in vivo time course transcriptomics, cellular reprogramming to TSC state, chemical induction of totipotent stem-cell-like state, and stem-cell-based embryo-like structures, have enriched our insights into the intricate molecular mechanisms and signaling pathways that define the mouse and human trophectoderm/TSC states. We delve into disparities between mouse and human trophectoderm/TSC fate establishment, with a special emphasis on the intriguing role of pluripotency in this context. Additionally, we re-evaluate recent findings concerning the potential of totipotent-stem-like cells and embryo-like structures to fully manifest the trophectoderm/trophoblast lineage's capabilities. Lastly, we briefly discuss the potential applications of induced TSCs in pregnancy-related disease modeling., Competing Interests: Declaration of interests Prof. Buganim holds a patent regarding the production of human TSCs with GOKM factors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A complete knockout of a single key pluripotency gene may drastically affect embryonic stem cell function and epigenetic reprogramming. In contrast, elimination of only one allele of a single pluripotency gene is mostly considered harmless to the cell. To understand whether complex haploinsufficiency exists in pluripotent cells, we simultaneously eliminated a single allele in different combinations of two pluripotency genes (i.e., Nanog +/- ;Sall4 +/- , Nanog +/- ;Utf1 +/- , Nanog +/- ;Esrrb +/- and Sox2 +/- ;Sall4 +/- ). Although these double heterozygous mutant lines similarly contribute to chimeras, fibroblasts derived from these systems show a significant decrease in their ability to induce pluripotency. Tracing the stochastic expression of Sall4 and Nanog at early phases of reprogramming could not explain the seen delay or blockage. Further exploration identifies abnormal methylation around pluripotent and developmental genes in the double heterozygous mutant fibroblasts, which could be rescued by hypomethylating agent or high OSKM levels. This study emphasizes the importance of maintaining two intact alleles for pluripotency induction., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The association of second malignancies in hairy cell leukemia (HCL) is well recognized. Most of these malignancies are either solid tumors or lymphoproliferative disorders rather than myeloproliferative disorders. But these malignancies are usually related to a complication of the drug treatment for HCL. The chronological sequence of HCL occurring after a hematological disorder is very rarely described. This report describes the first case, to our knowledge, of a patient who developed HCL five years after essential thrombocythemia that was treated with oral cytoreductive agents. Pathogenesis of the coexistence of both diseases is discussed.

We describe a 16-year-old girl with aplastic anemia who, 1 year after initial diagnosis developed a refractory state to platelet transfusions due to alloimmunization and resulting in severe bleeding. Treatment with cyclosporin, initially prescribed as treatment of the bone marrow failure, resulted in prompt decrease in lymphocytotoxic antibodies, which paralleled a marked improvement in platelet recovery. To our knowledge, such a dramatic effect of cyclosporin on alloimmunization has not been previously reported and merits further attention.