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
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.
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.
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.
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.
Mechanisms of BCR-ABL in the pathogenesis of chronic
myelogenous leukaemia. Ren R. Nat Rev Cancer. 2005 Mar;5(3):172-83.
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.
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.
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.
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.
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: August 6, 2010.