Blood cell development depends on precisely controlled gene expression programs that govern the commitment and maturation of progenitor cells along specific lineages. In addition to transcription factors that regulate gene expression during the course of lineage commitment, intact cell cycle control mechanisms are critical to normal blood cell maturation. In a mouse knock-in model developed to study the physiologic consequences of dysregulated cyclin E, a protein that regulates S-phase entry, we found abnormal red blood cell maturation, with increased proliferation, apoptosis, and dysplastic morphologies in erythroid progenitors. These features are characteristics of hematopoietic cells of patients with early-stage myelodysplastic syndromes (MDS). We hypothesize that proper regulation of cyclin E is critical during normal hematopoiesis and that deregulated cell cycle controls contribute to the pathogenesis of blood diseases such as MDS and leukemia. The Fbw7 ubiquitin ligase is a major regulator of cyclin E activity and also controls the abundance of other important oncogenic proteins involved in cell growth and proliferation. Fbw7 loss-of-function mutations are found in acute leukemias, and mutations in signaling pathways associated with myelodysplasia and leukemias can impair Fbw7- mediated cyclin E degradation. We recently found that the p53 tumor suppressor is activated in erythroid progenitor cells in a DNA damage-type response to impaired Fbw7-mediated cyclin E degradation. In the proposed studies comprising Aim 1, we will first define how high cyclin E and the molecular response it evokes alters normal erythroid cell maturation. MDS is a heterogeneous group of blood diseases caused by hematopoietic stem cell defects. In studies proposed in Aim 2, we will test the hypothesis that Fbw7-mediated cyclin E regulation critically maintains normal hematopoietic stem cell function. Mutations in p53 are found in advanced stage MDS, which is associated with progression to frank leukemia.
In Aim 3, we will test the hypothesis that compromised p53 function cooperates with dysregulated cyclin E in hematopoietic progenitors to induce neoplasia in vivo. We will develop mouse marrow transplantation models to test this hypothesis by disabling p53 function in cyclin E knock-in hematopoietic cells, either directly by allelic deletion or indirectly via dysregulated expression of another oncogenic substrate of Fbw7, c-Jun.

Public Health Relevance

Myelodysplastic syndromes and acute leukemias that evolve from MDS are especially difficult to treat, usually causing death. There is urgent need for a better understanding of the molecular pathogenesis of these diseases, one long-term goal of these studies, in order for more effective treatment strategies to be devised.

Public Health Relevance

Myelodysplastic syndromes and acute leukemias are malignant diseases of the blood, and in older adults these diseases are especially difficult to treat and usually cause death. There is urgent need for understanding the different ways in which these diseases occur so that better treatments can be developed in the future. The investigators recently found that one of the proteins that controls cell division (called "cyclin E"), when it is abnormally regulated, causes defects in blood cell development, some of which resemble those found in some patients with myelodysplasia. The investigators now propose to study how high cyclin E levels cause these blood cell defects and contribute to bone marrow failure and cancers.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098608-03
Application #
8309057
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$373,534
Indirect Cost
$126,034
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Glaubach, Taly; Minella, Alex C; Corey, Seth J (2014) Cellular stress pathways in pediatric bone marrow failure syndromes: many roads lead to neutropenia. Pediatr Res 75:189-95
Xu, Y; Swartz, K L; Siu, K T et al. (2014) Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism. Oncogene 33:3161-71
Siu, Ka Tat; Xu, Yanfei; Swartz, Kelsey L et al. (2014) Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7-mediated cyclin E regulation. Mol Cell Biol 34:3244-58
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Olive, Virginie; Sabio, Erich; Bennett, Margaux J et al. (2013) A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis. Elife 2:e00822
Siu, Ka Tat; Rosner, Marsha Rich; Minella, Alex C (2012) An integrated view of cyclin E function and regulation. Cell Cycle 11:57-64
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