Acute myeloid leukemia (AML) is a heterogeneous group of genetically diverse hematopoietic malignancies with variable responses to treatment. Around 10% of AMLs are involved in chromosomal rearrangements of the mixed lineage leukemia (MLL) gene with over 60 fusion partners. The critical feature of MLL-rearrangements is the generation of a chimeric transcript consisting of 5' MLL and 3' sequences of a partner gene (80% involving AF9, AF6, AF10, ELL or ENL in AML). The prognosis of MLL-associated leukemia is poor. A group of important oncogenes, including homeobox A (HOXA) genes, MEIS1, FLT3, MYB, and MYC, are frequently up-regulated in MLL-associated leukemias, and play a key role in the self-renewal of leukemia stem cells (LSCs) carrying MLL-rearrangements. However, clinically significant therapies have not been developed to effectively target these genes yet. Thus, better understanding of the molecular mechanisms underlying the pathogenesis of MLL-associated leukemia, and the development of effective therapeutic strategies based on such understanding, are urgently needed. MicroRNAs (miRNA) are a class of small, non- coding RNAs that play important roles in post-transcriptional gene regulation. Very recently, we reported that miR-150 is significantly down-regulated in most AML cases, and its repression is critical for MLL-AF9-mediated cell transformation and leukemogenesis; miR-150 functions as a pivotal tumor-suppressor gatekeeper in the MLL?fusion/MYC/LIN28-miR-150?FLT3/MYB/HOXA9/MEIS1 signaling circuit, through targeting FLT3/MYB directly and MYC/LIN28/HOXA9/MEIS1 indirectly (Jiang X., et al. Cancer Cell. 2012). Hypothesis: miR-150 is required for both development and maintenance of MLL-rearranged AMLs and for the self-renewal of the relevant LSCs. Therefore, the restoration of miR-150 expression/function holds significant potential to be clinically applicable to treat this type of presently therapy-resistant disease.
Specific Aims : 1) To determine whether repression of miR-150 is required for both development and maintenance of MLL-rearranged AMLs; 2) To determine whether repression of miR-150 is required for the self- renewal of LSCs of MLL-rearranged AMLs; and 3) To determine whether restoration of the expression/function of miR-150 (delivered by nanoparticles) is an effective new strategy for treating MLL-rearranged AMLs. Study Design: 1) We will use mouse bone marrow transplantation (BMT) models to determine whether ectopic expression of miR-150 can significantly inhibit both development and maintenance of all five major sub- types of MLL-rearranged AMLs (i.e., MLL-AF9, -AF6, -AF10, -ELL and -ENL). 2) We will conduct both competitive repopulation and limiting dilution assays to determine whether ectopic expression of miR-150 can significantly inhibit the self-renewal of relevant LSCs. 3) We will develop novel targeted nanoparticles based on FLT3L (FLT3 ligand)-directed dendrimers complexed with miR-150 oligos, followed by assessment of their specificity and efficacy in targeting/treating MLL-rearranged AMLs both in vitro and in vivo.
Around 10% of acute leukemias, including ~80% of all infant acute leukemia, carry a chromosomal rearrangement involving the MLL (mixed lineage leukemia) gene located on human chromosome 11, and the majority of patients cannot be cured with contemporary treatment; therefore, better understanding of the molecular mechanisms underlying the pathogenesis of the MLL-associated leukemia, and the development of effective therapeutic strategies based on such understanding, are urgently needed. The major goal of this proposal is to determine whether the repression of miR-150, a microRNA (miRNA) that is significantly down-regulated in most acute myeloid leukemia (AML) cases, including those carrying MLL-rearrangements, is required for the induction/development and maintenance of the MLL-rearranged leukemia and for the self- renewal of relevant leukemia stem cells (LSCs), and to determine whether restoring the expression/function of miR-150 using targeted nanoparticles is an effective new strategy for treating MLL-rearranged AMLs. Thus, this project will not only shed new light on our understanding of the pathological role and functional mechanism(s) of miR-150 and of the molecular mechanisms underlying the development, maintenance, and LSC self-renewal of MLL-rearranged leukemia, but also may lead to the development of a specific and effective novel therapeutic approach to treat this presently therapy-resistant disease using a targeted nanoparticle system.
|Jiang, Xi; Hu, Chao; Ferchen, Kyle et al. (2017) Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nat Commun 8:2099|
|Li, Zejuan; Weng, Hengyou; Su, Rui et al. (2017) FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. Cancer Cell 31:127-141|
|Li, Jing; Volk, Andrew; Zhang, Jun et al. (2017) Sensitizing leukemia stem cells to NF-?B inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling. Oncotarget 8:8420-8435|
|Wang, Yungui; Skibbe, Jennifer R; Hu, Chao et al. (2017) ALOX5 exhibits anti-tumor and drug-sensitizing effects in MLL-rearranged leukemia. Sci Rep 7:1853|
|Deng, Xiaolan; Su, Rui; Feng, Xuesong et al. (2017) Role of N6-methyladenosine modification in cancer. Curr Opin Genet Dev 48:1-7|
|Jiang, Xi; Hu, Chao; Arnovitz, Stephen et al. (2016) miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. Nat Commun 7:11452|
|Jiang, Xi; Bugno, Jason; Hu, Chao et al. (2016) Eradication of Acute Myeloid Leukemia with FLT3 Ligand-Targeted miR-150 Nanoparticles. Cancer Res 76:4470-80|
|Myung, Ja Hye; Tam, Kevin A; Park, Sin-jung et al. (2016) Recent advances in nanotechnology-based detection and separation of circulating tumor cells. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:223-39|
|Huo, Dezheng; Clayton, Wendy M; Yoshimatsu, Toshio F et al. (2016) Identification of a circulating microRNA signature to distinguish recurrence in breast cancer patients. Oncotarget 7:55231-55248|
|Li, Zejuan; Chen, Ping; Su, Rui et al. (2016) PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease. Cancer Res 76:619-29|
Showing the most recent 10 out of 20 publications