To promote faithful propagation of the genetic material during sexual reproduction, meiotic chromosomes undergo specialized morphological changes that ensure accurate segregation of homologous chromosomes. The molecular mechanisms that establish the meiotic chromosomal structures are largely unknown. We describe a mutation in a recently identified Histone H2A kinase, nhk-1, in Drosophila that leads to female sterility due to defects in the formation of the meiotic chromosomal structures. The metaphase I arrest and the karyosome, a critical prophase I chromosomal structure, require nucleosomal histone kinase-1 (NHK-1) function. The defects are a result of failure to disassemble the synaptonemal complex and to load condensin onto the mutant chromosomes. Embryos laid by nhk-1 −/− mutant females arrest with aberrant polar bodies and mitotic spindles, revealing that mitosis is affected as well. We analyzed the role of Histone H2A phosphorylation with respect to the histone code hypothesis and found that it is required for acetylation of Histone H3 and Histone H4 in meiosis. These studies reveal a critical role for histone modifications in chromosome dynamics in meiosis and mitosis.
The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways. (Blood. 2011;118(5):1264-1273) IntroductionDevelopmental pathways are generally viewed as a series of binary decisions with few opportunities for pleiotropy. However, this may limit adaptive decisions for development in adult tissues in response to environmental stressors.In the hematopoietic hierarchy, the various lymphoid and myeloid blood cell lineages originate from HSCs through successive cell fate decisions. 1,2 Purification of different progenitor populations that are based on multiple cellular markers and clonal analyses has yielded several potential models for hematopoietic development. [3][4][5][6][7] In particular, the origin of megakaryocyteerythrocyte progenitors (MEPs) is unclear. Several lines of evidence indicate that MEPs develop from committed myeloid progenitors, 5,7,8 whereas others have suggested that MEPs may arise directly from HSCs before their commitment to lymphoid/ myeloid lineages. 3,4,6 Of note, a number of genes involved in megakaryocyte-erythrocyte development, including Runx1, Tal1, or c-Myb, also play important roles in HSC biology. 9 The molecular basis for cell fate decisions made by HSCs for lineage commitment are not well understood. However, it is plausible that there are opportunities for MEP lineage commitment at more than 1 branch point in the hematopoietic developmental hierarchy. A precise understanding of the roadmap of hematopoietic development of MEPs may be of value both for the treatment of hematopoietic malignancies involving this lineage and in developing strategies to enhance regenerative platelet production.The NOTCH signaling pathway is highly conserved among multicellular organisms and has been shown to participate in a broad range of developmental processes in part through the regulation of cell fate decisions. 10 Several observations highlight the importance of tight regulation of NOTCH pathway activity during hematopoietic development. These include the causal role of Notch1-activating mutations in...
The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRAS G12D -associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor-independent KRAS G12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.
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