T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a very aggressive malignancy. Targetable molecules/pathways of T-ALL are limited because of an insufficient understanding of its genetics and biology. The applicant's long-term goal is to advance the knowledge of the molecular processes for the development, proliferation and survival of T-ALL cells, and to translate the identification of molecular targets into better treatment of T-ALL. Inactivation of PTEN, INK4a and ARF tumor suppressor genes is among the most frequent genetic events in T-ALL. We hypothesized that inactivated Pten and Ink4a/Arf tumor suppressors cooperate in the tumorigenesis of T-ALL. Aberrant molecular pathway/genetic changes in T-ALL, including certain microRNAs, play a role in the pathogenesis of T-ALL, and combined targeted therapy with NOTCH1 and PI3K/mTOR inhibitors, and micorRNAs is effective for T-ALL. Our preliminary studies revealed the mouse T-ALL resembled the human counterparts genetically, histologically and immunophenotypically.
In Aim 1, we will determine the impact of INK4a or Arf deficiency on the development of Pten null T-ALL. We plan to evaluate 1) T-ALL biology at the organismal and patho-histologic levels and 2) to determine if the differential tumor suppressor mutational spectrum impacts this effect.
In Aim 2, we will characterize Pten and/or Ink4a/Arf deficient T-ALL molecularly. In this aim, we will evaluate (1) the status of known critical genes/pathways involved in the pathogenesis of T-ALL deficient for Pten, Pten and Ink4a/Arf, Ink4a/Arf, Pten and Ink4a, Pten and Arf, Ink4a, and Arf, (2) The expressions levels of miR-150 and -155 in the mouse T-ALL, (3) Functional consequences of expressed miR-150 and -155, and (4) the pertinent targets of miR-150 and -155 in the pathogenesis of T-ALL.
In Aim 3, we will evaluate the effects of targeted therapies on Pten and/or Ink4a/Arf deficient T-ALL. We will determine (1) the effects of blocking PI3K/mTOR pathways, (2) the effects of GSI, and (3) the combinatorial effects of PI3K/mTOR inhibitor and GSI on our T-ALL models, (4) the combinatorial effects of PI3K/mTOR inhibitor and GSI on human T-ALL, and (5) the effects of restoring miR-155 and -150 expressions on T-ALL. These studies will likely provide insight into critical genes in the pathogenesis of T-ALL, and provide a platform for effective targeted therapies of T-ALL.

Public Health Relevance

T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a malignant neoplasm of T-lymphoblasts. However, conventional chemotherapy has been far from satisfactory, predominantly due to recurrent/refractory T-ALL. We will look into the role of criticl genes, Pten and Ink4a/Arf, in the pathogenesis of T-ALL, and options for targeted therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA164346-03
Application #
8685001
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Mccarthy, Susan A
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Hospitals
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
Xu, Shengfeng; Wu, Xiao; Wu, Ling et al. (2017) Abro1 maintains genome stability and limits replication stress by protecting replication fork stability. Genes Dev 31:1469-1482
Zang, Shengbing; Li, Jia; Yang, Haiyan et al. (2017) Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis. J Clin Invest 127:2998-3012
Yuan, T; Yang, Y; Chen, J et al. (2017) Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia 31:2355-2364
Kim, Jongchan; Siverly, Ashley N; Chen, Dahu et al. (2016) Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways. Cancer Res 76:6424-6435
Lee, Hyemin; Dai, Fangyan; Zhuang, Li et al. (2016) BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21. Oncotarget 7:19134-46
Riley, M F; You, M J; Multani, A S et al. (2016) Mdm2 overexpression and p73 loss exacerbate genomic instability and dampen apoptosis, resulting in B-cell lymphoma. Oncogene 35:358-65
Sergeeva, A; He, H; Ruisaard, K et al. (2016) Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo. Leukemia 30:1475-84
Tashakori, Mehrnoosh; Zhang, Yun; Xiong, Shunbin et al. (2016) p53 Activity Dominates That of p73 upon Mdm4 Loss in Development and Tumorigenesis. Mol Cancer Res 14:56-65
Pan, D; Jiang, C; Ma, Z et al. (2016) MALT1 is required for EGFR-induced NF-?B activation and contributes to EGFR-driven lung cancer progression. Oncogene 35:919-28
Wang, Lei; Xiong, Hua; Wu, Fengxia et al. (2014) Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep 8:1461-74

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