Acute myeloid leukemia patients with variant or unusual translocations involving chromosomes 8 and 21 - A comprehensive cytogenetic profiling of three cases with review of literature.

Background: t(8;21)(q22;q22) is the most frequent recurrent translocation in acute myeloid leukemia (AML) resulting in an in-frame fusion of RUNX1/RUNX1T1 that regulates various genes involved in the signaling pathways. This leukemogenic alteration is usually associated with a favorable clinical outcome. Variants of t(8;21) can be formed involving a third or fourth chromosome in ~3-4% of t(8;21)-AML. Due to the rarity of variant t(8;21), its clinicopathological features and prognostic significance are still unclear. Here we present three AML cases with cryptic rearrangements of chromosomes 8 and 21 without standard RUNX1/RUNX1T1. Materials and Methods: Conventional karyotyping and fluorescence in situ hybridization and/or spectral karyotyping of the pretreatment bone marrow aspirate of de novo AML patients were performed to delineate chromosomal abnormalities. Results: We identified three cases with novel variants of t(8;21); der(13)t(8;21;13), isodicentric derivative 8 with chromosome 21[,+idicder(8)(q11.1)t(8;21)(q22;q11.1)] and der(21)t(8;12;21)(q22;q?;q22). Conclusion: AML with t(8;21)(q22;q22);RUNX1-RUNX1T1 forms a distinct WHO subcategory and hence the identification of variants or unusual translocations associated with t(8;21) deserves more attention. Contribution to the variant/ unusual t(8;21) database will further refine the risk stratification and may help to significantly advance the current treatment regimen.

A novel SRY gene mutation c.266 A>T (p.E89V) in a 46,XY complete gonadal dysgenesis patient.

The SRY gene is considered as the key player in the male sexual differentiation and developmental pathway. SRY gene mutations account for ~15% of 46,XY disorders of sexual development patients, and majority of them resides within the HMG domain of the protein. In this study, we report a novel missense mutation within the HMG domain of SRY gene, and an A-to-T transition causes E89V amino acid substitution in a 15-year-old female patient with 46,XY karyotype and complete gonadal dysgenesis. Moreover, three-dimensional analysis of protein-DNA complex showed that the replacement of highly hydrophilic glutamic acid residue with a hydrophobic residue like valine would have an impact on the structure of protein. In conclusion, we identified a novel SRY mutation in a 46,XY female patient with complete gonadal dysgenesis, and based on the protein modelling, we propose that the identified mutation could impair normal function of the SRY protein.

Differential gene expression changes and their implication on the disease progression in patients with Chronic Myeloid Leukemia.

The molecular mechanisms responsible for disease progression of CML are not conclusive. The main functional changes associated with disease evolution in CML was high proliferation rate, decreased apoptosis, blockade of differentiation, and strong resistance to chemotherapeutic agents. The current study analyzed the relative expressional profiles of genes related with proliferation, apoptosis, differentiation, and resistance to chemotherapeutic agents such as c-MYC, BAD, BCL-2, C/EBPα/-ß and ABCB1 respectively in different clinical stages of CML by SYBR Green I quantitative real-time (qRT) PCR. We selected a total of 183 CML patients and 30 healthy control samples. The study populations were classified into four groups, including de novo CML-CP (50/183), CML-AP (32/183), CML-BC (51/183) and Imatinib Mesylate or IM resistant CML-CP (50/183) groups. qRT PCR analysis revealed that significant overexpression of c-MYC, ABCB1 and BCL-2 was observed in advanced phases and IM resistant CP of CML compared to healthy controls. Likewise, the mean expression level of BAD, C/EBPα/-ß genes were found to be significantly down regulated. Present study concluded that the complex interplay of several candidate genes like overexpression of c-MYC, ABCB1, BCL-2 and down regulation of BAD, C/EBPα/-ß played a significant role in the disease evolution and development of drug resistant in CML.

Enigmatic Inv(9): A Case Report on Rare Findings in Hematological Malignancies.

INTRODUCTION: Inversion of chromosome 9 had been widely discussed among geneticists and evolutionary biologists because of its significant impact on various hereditary disorders and in the evolution of man. The role of such inversions in human disease evolution is an area hitherto unclear. CASE PRESENTATION: We present the case of a chronic myeloid leukemia (CML) patient who showed intermittent relapse on treatment, with a rare appearance of clones with dual inversion (9) breakpoints [inv(9)(p22q34); inv(9)(p11q21)]. We also present the first report of inv(9)(p11,q13) as the sole abnormality in a patient with chronic myeloproliferative disorder(CMPD). Both the patients registered in 2012 and were from Kerala, India. CONCLUSIONS: Both the cases discussed in our study have inv(9) as the sole abnormality and are found to confer a relatively poor prognosis.