Evolution of abnormal hematopoietic clones with acquired genomic defects is one of the central events in the pathophysiology of MDS. Chromosomal or genetic abnormalities have significant prognostic and therapeutic implications. However, it remains unclear which karyotypic changes represent disease-specific lesions or whether they evolved as a consequence of the aging process. It is likely that patients with a """"""""normal"""""""" karyotype by traditional cytogenetics harbor smaller Iesions detectable if more precise methods were used. In general, the mechanisms leading to acquisition of chromosomal damage may include weakening of the DNA repair machinery and chromosomal instability. In addition, loss of telomeric sequences may render the chromosomes sensitive to rearrangement and loss although shortening of telomeres may also be a reflection of impaired DNA repair. We have developed technologies to study the relation of chromosomal changes and DNA repair defects in patients with MDS and age-matched elderly individual including targeted expression arrays and array-based comparative genomic hybridization (A-CGH). We hypothesize that """"""""cryptic"""""""" chromosomal lesions can be detected by A-CGH in a proportion of MDS patients who have normal metaphase cytogenetics. The presence of increased numbers of these changes may reflect an acquired predisposition to genomic damage due to defects in gene repair, mitotic machinery and/or excessive telomere shortening. Such changes may be present in freshly isolated hematopoietic progenitor cells or be detectable upon induction through clastogenic stress in culture. We will determine whether karyotypic abnormalities are present in MDS patients with normal metaphase cytogenetics and whether these changes can also be encountered during the normal aging process. Subsequently, using a quantitative PCR assay, we will investigate whether telomere shortening in hematopoietic progenitor cells correlates with the presence of chromosomal defects. Telomere length and frequency of chromosomal damage between hematopoietic and mesenchymal progenitor cells in patients with MDS and elderly individuals will be compared to determine whether the observed changes are restricted to the hematopoietic compartment. Finally, patterns of repair and chromosomal instability (CIN)-associated gene expression will be compared in patients and controls with and without chromosomal lesions in freshly isolated cells progenitor cells and upon induction following culture in the presence of clastogenic agents.
| Hosono, Naoko; Makishima, Hideki; Mahfouz, Reda et al. (2017) Recurrent genetic defects on chromosome 5q in myeloid neoplasms. Oncotarget 8:6483-6495 |
| Yoshizato, Tetsuichi; Nannya, Yasuhito; Atsuta, Yoshiko et al. (2017) Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood 129:2347-2358 |
| Jobe, F; Patel, B; Kuzmanovic, T et al. (2017) Deletion of Ptpn1 induces myeloproliferative neoplasm. Leukemia 31:1229-1234 |
| Molenaar, R J; Thota, S; Nagata, Y et al. (2015) Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 29:2134-42 |
| Kurtovic-Kozaric, A; Przychodzen, B; Singh, J et al. (2015) PRPF8 defects cause missplicing in myeloid malignancies. Leukemia 29:126-36 |
| Ruffalo, Matthew; Husseinzadeh, Holleh; Makishima, Hideki et al. (2015) Whole-exome sequencing enhances prognostic classification of myeloid malignancies. J Biomed Inform 58:104-113 |
| Shen, Wenyi; Clemente, Michael J; Hosono, Naoko et al. (2014) Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest 124:4529-38 |
| Hosono, N; Makishima, H; Jerez, A et al. (2014) Recurrent genetic defects on chromosome 7q in myeloid neoplasms. Leukemia 28:1348-51 |
| Makishima, Hideki; Yoshida, Kenichi; Nguyen, Nhu et al. (2013) Somatic SETBP1 mutations in myeloid malignancies. Nat Genet 45:942-6 |
| Clemente, Michael J; Przychodzen, Bartlomiej; Jerez, Andres et al. (2013) Deep sequencing of the T-cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes. Blood 122:4077-85 |
Showing the most recent 10 out of 48 publications
