A Key Commitment Step in Erythropoiesis Is Synchronized with the Cell Cycle Clock through Mutual Inhibition between PU.1 and S-Phase Progression

Pop, Ramona; Shearstone, Jeffrey R.; Shen, Qichang; Liu, Ying; Hallstrom, Kelly N.; Koulnis, Miroslav; Gribnau, Joost; Socolovsky, Merav

doi:10.1371/journal.pbio.1000484

Cited by 161 publications

(244 citation statements)

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“…CD71 + Ter119 − proerythroblasts represent a critical transitional stage marked by Epo dependency (51) and elevated DNA replication (45), both shown here to require high LMO2 protein expression. Conversely, terminal erythroid differentiation to the CD71 − Ter119 + stage is necessarily coordinated with growth arrest (13, 51), which we now show to be favored by Lmo2 downregulation, in agreement with previous work indicating that LMO2 overexpression prevents terminal erythroid differentiation (11).…”

Section: Discussionmentioning

confidence: 85%

“…Cell cycle is highly regulated in the erythroid lineage because ∼80% of primary proerythroblasts (E1 stage; Fig. 3A) are in S phase, exactly at the onset of erythropoietin (Epo) dependence (45), and this proportion sharply drops at the E3 and E4 stages of terminal differentiation. We observed that the E1 population segregated into cells with high and low endogenous LMO2 protein levels (Fig.…”

Section: Lmo2 Expression Levels Control the Rate Of Dna Synthesis Andmentioning

confidence: 99%

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The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.M ore than 70% of recurring chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) involve transcription factors that are master regulators of cell fate. These oncogenic transcription factors determine the gene signature and leukemic cell types (1). Whether these DNA-bound factors may have additional roles beyond modulating gene expression remains unknown. LMO2, a 17-kDa protein defined by tandem zinc finger domains, is an essential nucleation factor that assembles a multipartite transcriptional regulatory complex on gene regulatory regions via direct interaction with the TAL1/SCL transcription factor, LDB1, and other DNA binding transcription factors (2-4, reviewed in refs. 5, 6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8, 9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs. 5, 6). Interestingly, Lmo2 down-regulation is required for terminal erythroid differentiation (11,12). Because commitment to terminal differentiation is coordinated with growth arrest (13), Lmo2 may have additional molecular functions that impede this critical step marked by growth cessation.In mouse models of T-ALL, LMO1 or LMO2 collaborates with SCL to inhibit the activity of two basic helix-loop-helix (bHLH) transcription factors that control thymocyte differentiation, E2A/ TCF3 and HEB/TCF12, causing differentiation arrest (reviewed in ref. 14). However, this inhibition is not sufficient, per se, for leukemogenesis, because both TAL1 and LYL1 inhibit E proteins but require interaction with LMO1/2 to activate the transcription of a self-renewal gene network in thymocytes (15,16) and to induc...

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Section: Discussionmentioning

confidence: 85%

Section: Lmo2 Expression Levels Control the Rate Of Dna Synthesis Andmentioning

confidence: 99%

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, it has been shown that the downregulation of p57 Kip2 (and the S-phase entry) commits the cells to erythropoietic differentiation, which is associated with the onset of erythropoietin dependence, activation of GATA-1 (a key erythroid transcriptional regulator), and a switch of chromatin conformation at the b-globin locus toward an active status. These findings identify an important role of p57 Kip2 as a master regulator of erythrocytic differentiation, distinct from its activity as a CDK inhibitor (98).…”

Section: P57 Kip2 Metabolismmentioning

confidence: 86%

“…It was recently shown that a novel linkage exists between cell cycle progression and red blood cell commitment, and that it occurs several cell division cycles before the exit from the cell cycle (98).…”

Section: P57 Kip2 Metabolismmentioning

confidence: 99%

p57Kip2 and Cancer: Time for a Critical Appraisal

Borriello

Caldarelli

Bencivenga

et al. 2011

Molecular Cancer Research

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p57Kip2 is a cyclin-dependent kinase inhibitor belonging to the Cip/Kip family, which also includes p21Cip1 and p27Kip1. So far, p57Kip2 is the least-studied Cip/Kip protein, and for a long time its relevance has been related mainly to its unique role in embryogenesis. Moreover, genetic and molecular studies on animal models and patients with Beckwith-Wiedemann syndrome have shown that alterations in CDKN1C (the p57Kip2 encoding gene) have functional relevance in the pathogenesis of this disease. Recently, a number of investigations have identified and characterized heretofore unexpected roles for p57Kip2. The protein appears to be critically involved in initial steps of cell and tissue differentiation, and particularly in neuronal development and erythropoiesis. Intriguingly, p27Kip1, the Cip/Kip member that is most homologous to p57Kip2, is primarily involved in the process of cell cycle exit. p57Kip2 also plays a critical role in controlling cytoskeletal organization and cell migration through its interaction with LIMK-1. Furthermore, p57Kip2 appears to modulate genome expression. Finally, accumulating evidence indicates that p57Kip2 protein is frequently downregulated in different types of human epithelial and nonepithelial cancers as a consequence of genetic and epigenetic events. In summary, the emerging picture is that several aspects of p57Kip2's functions are only poorly clarified. This review represents an appraisal of the data available on the p57Kip2 gene and protein structure, and its role in human physiology and pathology. We particularly focus our attention on p57Kip2 changes in cancers and pharmacological approaches for modulating p57Kip2 levels. Mol Cancer Res; 9(10); 1269–84. ©2011 AACR.

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“…The downregulation of PU.1 was reported to play a role in the pathogenesis of various hematological malignancies, including Acute Myeloid Leukemia (AML) [2], multiple myeloma [3] and Myelodysplastic Syndrome (MDS) [4]. PU.1 is also normally present in immature erythroid cells [5], and several reports have indicated that their downregulation is required for erythroid terminal differentiation [6][7][8][9].…”

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confidence: 99%