Lalitha Nagarajan, Ph.D.

Molecular mechanisms underlying normal growth and differentiation are altered in cancer. Activation of growth-promoting genes and inactivation of differentiation and growth-arrest genes represent important steps in the evolution of a malignant clone. Normal blood cell formation and leukemia offer attractive systems for understanding malignant transformation because of the well-defined stages of blood cell maturation, the distinct subsets found in normal circulation, and the recurrent chromosomal alterations in leukemia. The clinical outcome of leukemic patients is tightly correlated with chromosomal abnormalities. Our goal is to establish how the normal pathways of hematopoietic growth arrest and differentiation are perturbed during malignant transformation. The research in my laboratory focuses on 2 major areas: deletions and translocations of chromosome 5q and the SMAD5 pathway in hematopoiesis and leukemia.Anomalies of chromosome 5q are associated with poor prognosis in leukemia pateints, suggesting that loss of regulatory genes from these loci facilitate malignant transformation. Recent work in our laboratory resulted in the isolation of a novel regulatory gene, SSDP2, that is disrupted in human leukemia. Current studies focus on understanding the functional consequence of this disruption.The SMAD5 gene, a transcriptional coactivator that transduces signals from the BMP family of peptides mediates commitment to hematopoietic differentiation in lower organisms. However, very little is known about this pathway in humans. We are interested in identifying target genes that are regulated by SMAD5 and determining how they in turn give rise to the multiple differentiated cell types found in human blood.

Recent publications

Liang H, Samanta S and Nagarajan L. (2005) SSBP2, a Candidate Tumor Suppressor Gene Induces Growth Arrest and Differentiation of Myeloid Leukemia Cells. Oncogene 24: 2625–2634.
Hejlik D and Nagarajan L. (2005) 5q deletion in myeloid leukemia cells HL60: An L1 element mediated instability. Cancer Genetics Cytogenetics 156:97–103.
Castro P, Liang H, Liang JC, Nagarajan L. (2002) A Novel, Evolutionarily Conserved Gene Family with Putative Sequence-Specific Single-Stranded DNA-Binding Activity Genomics 80:78–85.
Guo W, Chan AP, Liang H, Wieder ED, Molldrem JJ, Etkin LD, Nagarajan L. (2002) A human Mix-like homeobox gene MIXL shows functional similarity to Xenopus Mix.1. Blood 100:89–95.
Liang H, Guo W, Nagarajan L (2000) Chromosomal mapping and genomic organization of an evolutionarily conserved zinc finger gene ZNF277. Genomics 66, 226–228.
Jiang YF, Liang H, Guo W, Kottickal LV, Nagarajan L (2000) Differential expression of a Novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia. Blood 95, 3945–3950.
Castro P, Liang JC, Nagarajan L (2000) Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. Blood 95, 2138–2143.
Zavadil J., Svoboda P., Liang H., Kottickal L.V., and Nagarajan L. (1999) An antisense transcript to SMAD5 expressed in fetal and tumor tissue. Biochem. Biophys. Res. Comm. 255:668–72.
Liang H., Fairman J., Claxton D.C., Nowell P.C. , Green E.D., and Nagarajan L. (1998) Molecular anatomy of chromosome 7q deletions in myeloid neoplasms:Evidence for multiple critical loci. Proc Natl Acad Sci USA 95:3781–378 5.
Helijk D.P., Kottickal L.V., Liang H., Fairman J., Davis T., Janecki T., Sexton D., Perry III W., Tavtigian S.V., Teng D.H.F. and Nagarajan L. (1997) Localization of SMAD5 and its evaluation as a candidate myloid tumor suppressor. Cancer Res 57, 3779–3783.
Fairman, J., Chumakov, I., Chinault, C., Nowell P., and Nagarajan L., (1995) Physical mapping of the critical region of loss in 5q- chromosome. Proc.Natl.Acad. Sci. USA 92:7406–7410.