Acute Myeloid Leukemia (AML) is a heterogeneous malignancy that arises from the bone marrow, resulting in less than 50% of patients with AML being cured. The molecular mechanisms of AML are not well understood.
The specific aims of my previous R01 grant addressed the overall hypothesis that the cAMP Response Element Binding Protein (CREB) contributes to leukemogenesis. In the initial funding period, we described the overexpression of CREB in AML. We successfully completed the three specific aims and demonstrated that 1) CREB is expressed in less differentiated normal hematopoietic stem and progenitor cells;2) CREB overexpression is associated with an increased risk of relapse and decreased event-free survival;3) overexpression of CREB in myeloid cells results in increased proliferation and survival in vitro;4) hMRP8-CREB transgenic mice develop myeloproliferative disease;and 5) CREB knockdown in vitro and in vivo inhibits leukemic progression but not long-term hematopoietic stem cell engraftment. In this revised competitive renewal application, we propose to examine the molecular pathways to understand the mechanism of CREB function in normal and aberrant hematopoiesis. We propose four specific aims.
In Aim 1, we will study the role of CREB on hematopoietic dynamics by transplanting bone marrow from CREB transgenic mice into lethally irradiated mice and assessing molecular changes in the myeloid compartment. Our collaborators and I found that the microRNA, miR-34b, recognizes a sequence in the 3'UTR of the CREB gene.
In Aim 2, we will characterize the regulation of CREB by the microRNA, miR-34b. Our preliminary data showed that Meis1 and Pbx1 are upregulated 33- and 28-fold by expression profiling. Meis1 and Pbx1 are direct targets of CREB. Thus, Aim 3 describes experiments to study the requirement of Meis1 and Pbx1 downstream of CREB. Finally, we identified sox4 and gfi1 in a retroviral insertional mutagenesis screen in which CREB transgenic mice were infected with the MOL4070LTR retrovirus. CREB transgenic mice infected with this retrovirus developed AML with a shortened latency compared to control mice.
In Aim 4, we will examine the role of sox4 and gfi1 as genes that cooperate with CREB and contribute to the development of AML. These studies will provide new insights into how CREB regulates normal hematopoiesis and contributes to leukemogenesis.
The goal of this R01 application is to study the role of CREB in the development of acute myeloid leukemia. This project is relevant to public health because it focuses on identifying new pathways and targets for development of drugs to treat AML. Therefore, results from this work will improve the quality of life of AML patients.
|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|
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