Leukemia is the most common form of childhood cancer. Children with acute myeloid leukemia (AML) have less than 50% overall survival despite aggressive chemotherapy and bone marrow transplantation. Therefore, it is critical to understand the molecular pathogenesis of AML. We demonstrated that CREB is overexpressed in bone marrow cells from patients with AML but not in normal bone marrow or bone marrow from patients without active leukemia. Furthermore, CREB overexpression was associated with an increased risk of relapse and decreased event-free survival in patients with AML. Our preliminary results suggest that AML is a heterogeneous disease that is not well understood. We hypothesize that there is an uncoupling of differentiation and CREB expression in myeloid leukemia cells. We propose to study the role of CREB in normal and malignant myeloid cells to identify novel mechanisms of leukemogenesis and improve our understanding of the molecular pathways regulating myeloid cell proliferation and differentiation.
In Specific Aim 1, we will characterize CREB expression and activation in primary normal myeloid cells and myeloid leukemia cells. Experiments are proposed to determine the expression of CREB in normal mouse embryos at different stages of hematopoietic development. We will also examine CREB expression in normal myeloid progenitor cells at different stages of myeloid differentiation. Finally, we will examine whether CREB is activated in primary leukemia cells.
In Specific Aim 2, we will further characterize the biological phenotype of CREB overexpression and down regulation in myeloid leukemia cell lines and primary normal myeloid cells. Our preliminary results demonstrated that CREB overexpression leads to increased proliferation and survival of myeloid leukemia cells. CREB down regulation using RNA interference (RNAi) suppresses the growth and survival of leukemia cells. To study signaling pathways upstream of CREB, we will overexpress activated kinases and use RNAi technology to inhibit expression of kinases.
In Specific Aim 3, we will characterize the phenotype of transgenic mice in which CREB overexpression is targeted to myeloid cells. Defects in hematopoiesis and development of leukemia will be determined in both CREB transgenic mice and a mouse bone marrow transplant model. These studies will define the role of CREB in both normal and malignant myelopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075826-02
Application #
6845697
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Chang, Henry
Project Start
2004-01-20
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$305,543
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Huang, W; Luan, C-H; Hjort, E E et al. (2016) The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia. Leukemia 30:1502-9
Dutta, Ritika; Tiu, Bruce; Sakamoto, Kathleen M (2016) CBP/p300 acetyltransferase activity in hematologic malignancies. Mol Genet Metab 119:37-43
Mitton, Bryan; Hsu, Katie; Dutta, Ritika et al. (2016) Small molecule screen for inhibitors of expression from canonical CREB response element-containing promoters. Oncotarget 7:8653-62
Mitton, B; Chae, H-D; Hsu, K et al. (2016) Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells. Leukemia 30:2302-2311
Rankin, Erinn B; Narla, Anupama; Park, Joseph K et al. (2015) Biology of the bone marrow microenvironment and myelodysplastic syndromes. Mol Genet Metab 116:24-8
Chae, H-D; Mitton, B; Lacayo, N J et al. (2015) Replication factor C3 is a CREB target gene that regulates cell cycle progression through the modulation of chromatin loading of PCNA. Leukemia 29:1379-89
Sakamoto, Kathleen M; Grant, Steven; Saleiro, Diana et al. (2015) Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab 114:397-402
Pigazzi, Martina; Manara, Elena; Bresolin, Silvia et al. (2013) MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation. Haematologica 98:602-10
Sandoval, Salemiz; Kraus, Christina; Cho, Er-Chieh et al. (2012) Sox4 cooperates with CREB in myeloid transformation. Blood 120:155-65
Mitton, Bryan; Cho, Er-Chieh; Aldana-Masangkay, Grace I et al. (2011) The function of cyclic-adenosine monophosphate responsive element-binding protein in hematologic malignancies. Leuk Lymphoma 52:2057-63

Showing the most recent 10 out of 37 publications