Chromosomal instability is a characteristic feature of myeloid malignancies and the preleukemic syndromes that predispose to these leukemias. My primary research interest is to elucidate the molecular basis for genomic instability in these diseases. We have accrued evidence that genomic instability in myeloid malignancies may be driven by a combination of ongoing constitutive DNA damage coupled with increased activity of the error-prone non homologous end-joining (NHEJ) pathway which results in improper repair of double strand breaks (DSB). This cycle of DNA damage and misrepair is driven by endogenous reactive oxygen species production, a likely source for genomic instability in myeloid leukemias and premalignant syndromes that introduces genomic changes into DNA and drives disease progression.
My group is actively pursuing the following goals:
1. To identify and characterize the protein complexes pre- and -post DNA damage at DSB responsible for increased DSB repair infidelity.
2. To determine the signal transduction pathways important in the creation of oxygen radicals in myeloid malignancies.
3. To determine whether error-prone NHEJ is associated with acquisition of chromosomal abnormalities in models for myeloid leukemic progression in i) mice and ii) human preleukemic syndromes.
4. To determine the role of DNA damage on abnormal chromatin changes in cancer.
5. To determine the role of DNA repair complexes in repair of regions of genomic instability, such as, fragile sites.
Although the models I have heretofore focused on are in leukaemias, the genomic instability mechanisms apply to all cancer progression models, and this will be taken forward with various collaborative endeavors.
Gaymes TJ, North PS, Brady N, Hickson ID, Mufti GJ, Rassool FV. Increased error-prone non homologous DNA end-joining - a proposed mechanism of chromosomal instability in Bloom's syndrome. Oncogene (2002). 21(16):2525-33.
Gaymes TJ, Mufti GJ, Rassool FV. Myeloid Leukemias have Increased Activity of the Non Homologous End-Joining Pathway and Concomitant DNA Misrepair that is Dependant on the Ku70/86 Heterodimer. Cancer Research (2002) 62, 2791-2797.
Cameron E, Mijovic A, Herman J, Baylin S, Pradhan A, Mufti GJ, and Rassool FV. P15INK4B is not mutated in adult familial myelodysplastic syndromes. Brit. J Haematology (2002) 119, 277-279.
Aktas D, Arno M, ,Mufti GJ, Rassool FV. Analysis of Chk2 in patients with myelodysplastic syndromes. Leukemia Research (2002) 26, 985-987.
Rassool FV. Double strand breaks and NHEJ pathways in leukemia. Cancer Letters (2003) 193, 1-9.
Brady N, Gaymes TJ, Cheung M, Mufti GJ, Rassool FV.
Increased NHEJ Activity in Myeloid Leukemias is Associated with Ongoing or Induced DNA Damage at Sites that Recruit Key NHEJ Proteins. Cancer Research (2003) 63, 1798-1805.
Rassool FV, North PS, Mufti GJ, and Hickson ID. Constitutive DNA damage is linked to DNA replication abnormalities in Bloomâs syndrome cells. Oncogene (2003) 22, 8749-8757.
Pradhan A, Mijovic A, Mills K, Cumber P, Westwood N, Mufti GJ and Rassool FV. Differentially Expressed Genes in Adult Familial Myelodysplastic Syndromes (MDS). Leukemia (2004) 3, 449-59
Rassool FV. Genetic rearrangements beget genomic instability. Blood (2004) 104: 3424-3425.
Gaymes TJ, Mufti GJ, Stephen Orr, Rassool FV. Histone Deacetylase Inhibitors (HDI) Induce DNA Damage and Repair: A Mechanism for HDI Dependent Apoptosis in Leukemia Cells. Molecular Cancer Research (2006) 4, 563-573.