''An exciting glance at key issues in contemporary hematopoiesis.'' -The Quarterly Review of Biology

The Second Edition of this successful title has been fully revised and updated and now includes expanded sections on normal and malignant haematopoiesis, offering a thorough review of the molecular and cellular processes involved in malignancy, developments in diagnostic techniques and treatment, concluding with discussion of treatment of individual diseases, late effects of therapy and supportive care. Short Contents

Transcription Factors Normal and Malignant Development of Blood Cells Katya Ravid and Jonathan Licht The role of transcription factors in activating specific genes in blood cells is an important facet of hematopoiesis. Equally important, however, is the pursuit of genes rearranged and aberrantly activated in leukemias (blood malignancies). Transcription Factors: Normal and Malignant Development of Blood Cells focuses on those major transcription factors involved in activation of lineage-specific gene expression during normal versus malignant development of specific blood lineages, as revealed from gene promoter studies, knockout of transcription factors in mice models, and the identification and characterization of chromosomal rearrangement in human blood leukemias. This complete digest of current transcription factor data offers comprehensive coverage of the myriad of transcription factors in blood cell development, composed by established experts in the field. In addition to updating the reader on the connection between chromosomal translocations involving transcription factors and cellular transformation leading to leukemia, Transcription Factors also reviews such subjects as: * Transcription factors and the megakaryocytic, myeloid, and erythroid lineages * Leukemias due to chromosomal translocations involving gene encoding transcription factors * Oncogenesis and hematopoiesis * In vivo studies of transcription factors implicated in hematopoiesis * And much more Appealing to both the researcher and the clinician in the field of hematology, Transcription Factors is a timely presentation of cell lineage development and sheds light on the processes involved in the development of specific leukemias. Providing insight into the study of transcription factors, readers will gain an understanding of mechanisms that lead to normal lineage commitment and terminal differentiation.

Recent studies have identified recurrent mutations in all components of the cohesin complex in acute myeloid leukemia and other myeloid malignancies, and, importantly, have shown these mutations to occur early in disease pathogenesis and in pre-leukemic hematopoietic stem cells. Here, we investigate the impact of these mutations on hematopoiesis and demonstrate that introduction of cohesin mutants into normal human hematopoietic stem and progenitor cells (HSPC) results in blocked differentiation and enforcement of stem cell programs both in vitro and in vivo. These effects were cell context dependent, restricted to immature HSPC populations. Cohesin mutants selectively increased chromatin accessibility and likelihood of occupancy at binding sites for transcription factors known to regulate HSPC including ERG, GATA2, and RUNX1 as measured by ATAC-Seq and ChIP-Seq. Furthermore, epistasis experiments showed that silencing of these transcription factors 2in which mutant cohesin impairs hematopoietic differentiation and aberrantly enforces stem cell programs through the modulation of HSPC chromatin accessibility and transcription factor activity.

DNA methylation is an epigenetic modification that regulates gene transcription. The addition of a methyl group to cytosine is catalyzed by a family of enzymes known as DNA methyltransferases (Dnmts). The three catalytically active Dnmts in humans and mice are Dnmt1, Dnmt3a, and Dnmt3b. DNA methylation is clinically relevant, as aberrations in the methylation landscape are a hallmark of nearly all human cancers. Cancer methylomes are typically characterized by genome wide hypomethylation and regional specific hypermethylation, both of which have been linked to alterations in gene expression. In order to understand the contribution of epimutations to the development of hematological malignancies we created several mouse models in which one or more Dnmt is deleted in hematopoietic stem cells and all downstream lineages. This allowed us to address the role of individual Dnmts in normal and malignant hematopoiesis. We found that Dnmts contribute to the cancer methylome through both de novo and maintenance methylation, and that activities of individual Dnmts seldom overlap with one another. We identified Dnmt1 as being critical for T cell development and maintenance of the tumor phenotype in T cell lymphomas. Furthermore, we identified Dnmt3a and Dnmt3b as critical tumor suppressor genes in the prevention of chronic lymphocytic leukemia in mice. Collectively, these studies provide insight into the effects of Dnmt deregulation in tumorigenesis.