CASE: A 60-year-old woman presented with abdominal discomfort and hyperleukocytosis. She was diagnosed as CML in the chronic phase with positive BCR-ABL1 transcripts. Due to the failure to obtain an optimal response with imatinib treatment, it was switched to nilotinib. She responded well to nilotinib initially and achieved complete haematological and cytogenetic responses, with undetectable BCR-ABL1 transcripts. However, in 4 years she developed molecular relapse. Mutation analysis which was done 70 months after commencement of nilotinib showed the presence of BCRABL1 kinase domain mutation with nucleotide substitution at position 1187 from Histidine(H) to Proline(P) (H396P). Currently, she is on nilotinib 400mg twice daily. Her latest molecular analysis showed the presence of residual BCR-ABL1 transcripts at 0.22%.
DISCUSSION/CONCLUSION: This case illustrates the importance of BCR-ABL1 mutation analysis in CML patients with persistent BCR-ABL1 positivity in spite of treatment. Early detection and identification of the type of BCRABL1 mutation are important to guide appropriate treatment options as different mutation will have different sensitivity to TKI.
METHODS: In this study, we generated whole genome sequences of eight clinical strains of Mtb that were isolated from the cerebrospinal fluid (CSF) of patients presenting with tuberculous meningitis (TBM) in Malaysia, and compared them to the genomes of H37Rv and other respiratory Mtb genomes either downloaded from public databases or extracted from local sputum isolates. We aimed to find genomic features that might be distinctly different between CSF-derived and respiratory Mtb.
RESULTS: Genome-wide comparisons revealed rearrangements (translocations, inversions, insertions and deletions) and non-synonymous SNPs in our CSF-derived strains that were not observed in the respiratory Mtb genomes used for comparison. These rearranged segments were rich in genes for PE (proline-glutamate)/PPE (proline-proline-glutamate), transcriptional and membrane proteins. Similarly, most of the ns SNPs common in CSF strains were noted in genes encoding PE/PPE proteins. Protein globularity differences were observed among mycobacteria from CSF and respiratory sources and in proteins previously reported to be associated with TB meningitis. Transcription factors and other transcription regulators featured prominently in these proteins. Homologs of proteins associated with Streptococcus pneumoniae meningitis and Neisseria meningitidis virulence were identified in neuropathogenic as well as respiratory mycobacterial spp. examined in this study.
DISCUSSION: The occurrence of in silico genetic differences in CSF-derived but not respiratory Mtb suggests their possible involvement in the pathogenesis of TBM. However, overall findings in this comparative analysis support the postulation that TB meningeal infection is more likely to be related to the expression of multiple virulence factors on interaction with host defences than to CNS tropism associated with specific genetic traits.