C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.

Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype.

Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating mutations are required for the initial phase of the disease (chronic phase, CP-CML). Some CP-CML patients acquire additional mutation(s) that transforms CP-CML to poor prognosis, hard to treat, acute myeloid or lymphoid leukemia or blast phase CML (BP-CML).

Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells.

The hierarchy of human hemopoietic progenitor cells that produce lymphoid and granulocytic-monocytic (myeloid) lineages is unclear. Multiple progenitor populations produce lymphoid and myeloid cells, but they remain incompletely characterized. Here we demonstrated that lympho-myeloid progenitor populations in cord blood - lymphoid-primed multi-potential progenitors (LMPPs), granulocyte-macrophage progenitors (GMPs) and multi-lymphoid progenitors (MLPs) - were functionally and transcriptionally distinct and heterogeneous at the clonal level, with progenitors of many different functional potentials present.

Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage.

Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations.

Whole transcriptome data analysis of mouse embryonic hematopoietic stem and progenitor cells that lack Geminin expression.

We performed cDNA microarrays (Affymetrix Mouse Gene 1.0 ST Chip) to analyze the transcriptome of hematopoietic stem and progenitor cells (HSPCs) from E15.5dpc wild type and Geminin (Gmnn) knockout embryos.

Geminin deletion increases the number of fetal hematopoietic stem cells by affecting the expression of key transcription factors.

Balancing stem cell self-renewal and initiation of lineage specification programs is essential for the development and homeostasis of the hematopoietic system. We have specifically ablated geminin in the developing murine hematopoietic system and observed profound defects in the generation of mature blood cells, leading to embryonic lethality. Hematopoietic stem cells (HSCs) accumulated in the fetal liver following geminin ablation, while committed progenitors were reduced.

Reduced Geminin levels promote cellular senescence.

Cellular senescence is a permanent out-of-cycle state regulated by molecular circuits acting during the G1 phase of the cell cycle. Cdt1 is a central regulator of DNA replication licensing acting during the G1 phase and it is negatively controlled by Geminin. Here, we characterize the cell cycle expression pattern of Cdt1 and Geminin during successive passages of primary fibroblasts and compare it to tumour-derived cell lines.

T cell proliferation and homeostasis: an emerging role for the cell cycle inhibitor geminin.

Thymic T cell differentiation to peripheral T cells aims to assist the generation of effector cells mediating adaptive immune responses. During this process, which takes place during embryogenesis and in adulthood, proliferation is coupled with changes in chromatin organization and transcription. Moreover, B and T lymphocytes start to proliferate and rapidly expand their numbers when activated following an encounter with an antigen.

Life without geminin.

The interplay of proliferation and differentiation is essential for normal development and organogenesis. Geminin is a cell cycle regulator which controls licensing of origins for DNA replication, safeguarding genomic stability. Geminin has also been shown to regulate cellular decisions of self-renewal versus commitment of neuronal progenitor cells.

Differential geminin requirement for proliferation of thymocytes and mature T cells.

Stem/progenitor cells coordinate proliferation and differentiation, giving rise to appropriate cell numbers of functionally specialized cells during organogenesis. In different experimental systems, Geminin was shown to maintain progenitor cells and participate in fate determination decisions and organogenesis. Although the exact mechanisms are unclear, Geminin has been postulated to influence proliferation versus differentiation decisions.

Cdt1 and Geminin in cancer: markers or triggers of malignant transformation?

Cdt1 and its inhibitor Geminin are important regulators of replication licensing. In normal cells, a critical balance between these two proteins ensures that firing of each origin along the genome will take place only once per cell cycle. Cdt1 overexpression in cell lines and animals leads to aberrant replication, activates DNA damage checkpoints and predisposes for malignant transformation.