Core C The cell culture will provide cell culture support for this Program Project. The assays we use can detect hematopoietic progenitors at various stages of differentiation and can distinguish between normal and leukemic colony-forming cells. These assays are well suited to address a major issue arising in this Program Project, namely the derivation ofthe cells responding to various anti-leukemic agents investigated in this P01. These assays will be used to investigate the role of extrinsic cytokines including granulocytemacrophage colony stimulating factor (GM-CSF) and c-Kit ligand in protecting CML progenitors from Imatinib (IM;Gleevec)-induces apoptosis using blood and marrow cells of both patients sensitive and resistant to Gleevec. These studies will be conducted in collaboration with Projects 4 and 5. Also, we will provide support to Project 5 in studying the effects of lipocalin and antisense 24p3 and BCR on Ph+ cell lines and on normal and brc-abl+ eariy and mature progenitors. In collaboration with Project 3 we will study whether disruption ofthe microenvironment-dedicated protection of CML progenitors will affect the sensitivity of CML colony-forming cells to protein kinase inhibitors and whether Bcl-2 inhibitors will potentiate the effects of protein kinase inhibitors. Thus, the Specific Aims are the following: 1) To investigate whether extrinsic stimulatory cytokines protect CML progenitors from apoptotic effect of IM and other protein kinase inhibitors in collaboration with Drs. Deininger (Project 4) and Arlinghaus (Project 5) 2) To study the effects of anti-24p3 and anti-NGAL antibodies and BCR (transduced by the lentivirus vector infection system) on CML cell lines and fresh CML and normal marrow cells in collaboration with Dr. Arlinghaus (Project 5). 3) To investigate how interruption ofthe interaction between the hematopoietic stroma and the CML clone would affect the sensitivity of normal and BCR-ABL+ progenitors to protein tyrosine kinase inhibitors. We will study the effect of agents that interrupt the interaction between SDF-1 and CXCR4, and the combination of tyrosine kinases and Bcl-2 inhibitors using a combination of hematopoietic stroma cultures, the long-term culture initiating cell (LTCIC) assay and donogenic assays, in collaboration with Dr. Andreeff (Project 3).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Eiring, A M; Page, B D G; Kraft, I L et al. (2015) Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia 29:586-97
Zhang, Weiguo; Gao, Chen; Konopleva, Marina et al. (2014) Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies. Clin Cancer Res 20:2363-74
Tao, Wenjing; Leng, Xiaohong; Chakraborty, Sandip N et al. (2014) c-Abl activates janus kinase 2 in normal hematopoietic cells. J Biol Chem 289:21463-72
Thall, Peter F; Nguyen, Hoang Q; Zohar, Sarah et al. (2014) Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome. J Am Stat Assoc 109:931-943
Mak, P Y; Mak, D H; Mu, H et al. (2014) Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML. Apoptosis 19:698-707
Jin, Ick Hoon; Liu, Suyu; Thall, Peter F et al. (2014) Using Data Augmentation to Facilitate Conduct of Phase I-II Clinical Trials with Delayed Outcomes. J Am Stat Assoc 109:525-536
Benjamini, Ohad; Kantarjian, Hagop; Rios, Mary Beth et al. (2014) Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. Leuk Lymphoma 55:2879-86
Havelange, Violaine; Ranganathan, Parvathi; Geyer, Susan et al. (2014) Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood 123:2412-5
Ohanian, Maro; Kantarjian, Hagop M; Quintas-Cardama, Alfonso et al. (2014) Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 14:155-162.e1
Zabriskie, Matthew S; Eide, Christopher A; Tantravahi, Srinivas K et al. (2014) BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 26:428-42

Showing the most recent 10 out of 220 publications