Ruibao Ren is on a leave of absence until late 2020.

Protein tyrosine kinases play critical roles in the signal transduction pathways essential for organismal development and cell transformation. We are interested in understanding the molecular mechanisms of signal transduction via protein tyrosine kinases and of such signaling processes in blood cell development and pathogenesis of leukemia.

We are currently focused on study the molecular biology of chronic myelogenous leukemia (CML), a human clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. The majority of cases of CML is associated with the Philadelphia chromosome, which is a result of a reciprocal translocation between chromosomes 9 and 22 that fuses Bcr-encoded sequences to a truncated c-abl gene. This chimeric gene produces a fusion protein, Bcr-Abl, in which the protein tyrosine kinase activity of Abl is increased. We have shown that expression of Bcr-Abl oncogene in bone marrow cells of mice by retrovirus transduction efficiently induces a myeoloproliferative disorder resembling human CML.

Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Identifying substrates of Bcr-Abl and elucidating the mechanisms by which Bcr-Abl targets specific substrates are therefore critical for understanding the neoplastic transformation by Bcr-Abl. Using biochemical and genetic approaches we are investigating how the Abl kinase select substrates and identifying Bcr-Abl binding proteins that are either regulators or substrates of the Abl kinase. We have identified interesting candidate proteins that interact with specific domains of Abl. We have shown that some of these binding proteins are substrates of Abl, and that the non-catalytic interactions between Abl and its substrates plays an important role on regulation of the protein phosphorylation. To further understand the complex biology of CML, we are using the murine CML model developed in our laboratory to study the roles and relative importance of the domains of Bcr-Abl, of its interacting proteins, of Bcr-Abl-activated signaling pathways, and of host factors such as hematopoietic growth factors in developing CML, as well as identifying the target cell(s) of Bcr-Abl that gives rise to the clinical phenotypes of CML by analyzing the oncogenic potential of Bcr-Abl in various hematopoietic cell types and the subsequent pathology that arises from each cell type. Our long term goal is to understand the regulation of the blood cell development and the molecular mechanisms by which Bcr-Abl disrupts the development of blood cells, as well as to identify novel therapies to cure leukemia.

Selected Publications:

Cooperation between deficiencies of IRF-4 and IRF-8 promotes both myeloid and lymphoid tumorigenesis. Jo SH, Schatz J, Acquaviva J, Singh H, Ren R. Blood. 2010 Jun 28. [abstract]

Palmitoylation of oncogenic NRAS is essential for leukemogenesis. Cuiffo B, Ren R. Blood. 2010 Apr 29;115(17):3598-605. [abstract]

IRF-4 functions as a tumor suppressor in early B-cell development. Acquaviva J, Chen X, Ren R. Blood. 2008 Nov 1;112(9):3798-806. [abstract]

Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Parikh C, Subrahmanyam R, Ren R. Cancer Res. 2007 Aug 1;67(15):7139-46. [abstract]

Targeted degradation of the AML1/MDS1/EVI1 oncoprotein by arsenic trioxide. Shackelford D, Kenific C, Blusztajn A, Waxman S, Ren R. Cancer Res. 2006 Dec 1;66(23):11360-9. [abstract]

Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice. Parikh C, Subrahmanyam R, Ren R. Blood. 2006 Oct 1;108(7):2349-57. Epub 2006 Jun 8. [abstract]

Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Ren R. Nat Rev Cancer. 2005 Mar;5(3):172-83. Review. [abstract]

Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice. Cuenco GM, Ren R. (2004) Oncogene. 23:569-79. [abstract]

Modeling the dosage effect of oncogenes in leukemogenesis. Ren R. (2004) Curr Opin Hematol. 11:25-34. [abstract]

The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model. Ren R. (2002) Oncogene, 21:8629-42. [abstract]

Dissecting the molecular mechanism of chronic myelogenous leukemia using murine models. Ren R. (2002) Leuk Lymphoma. 43:1549-61. [abstract]

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. Cuenco GM, Ren R. (2001) Oncogene, 20:8236-48. [abstract]

The NH2-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Zhang X, R. Subrahmanyam, R. Wong, A. W. Gross and R. Ren. 2001. Mol. Cell. Biol. 21:840-853. [abstract]

The SH2 domain of Bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype. Zhang X, R. Wong, S. X. Hao, W. S. Pear, and R. Ren. 2001. Blood. 97:277-287. [abstract]

Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a novel model for human AML. Cuenco, G. M., G. Nucifora, and R. Ren. 2000. Proc. Natl. Acad. Sci. USA. 97: 1760-1765. [abstract]

Bcr-Abl has a greater intrinsic capacity than v-Abl to induce the neoplastic expansion of myeloid cells. Gross AW, Ren R. (2000) Oncogene. 19:6286-96.

 

Last reviewed: January 12, 2018.