ABSTRACT
OBJECTIVES: Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples are used for this purpose; however, this approach is site-limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that is not site-limited, but equally challenging. METHODS: While majority of current data comes from short-term studies, we present a long-term study on blood-based MRD monitoring using tumor-specific cell-free DNA detection by ASO-qPCR. One hundred and twelve patients were enrolled into the study, but long-term sampling and analysis were feasible only in 45 patients. RESULTS: We found a significant correlation of quantity of tumor-specific cell-free DNA levels with clinically meaningful events [induction therapy (P = .004); ASCT (P = .012)]. Moreover, length of cfDNA fragments is associated with better treatment response of patients. CONCLUSIONS: These results support the concept of tumor-specific cell-free DNA as a prognostic marker.
Subject(s)
Biomarkers, Tumor , Circulating Tumor DNA , Multiple Myeloma/diagnosis , Multiple Myeloma/genetics , Combined Modality Therapy , Disease Management , Flow Cytometry , Humans , Immunoglobulin Heavy Chains/genetics , Multiple Myeloma/therapy , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Outcome Assessment, Health Care , Polymerase Chain Reaction , Treatment OutcomeABSTRACT
Congenital heart defects, dysmorphic facial features and intellectual developmental disorders (CHDFIDD) syndrome in humans was recently associated with mutation in CDK13 gene. In order to assess the loss of function of Cdk13 during mouse development, we employed gene trap knock-out (KO) allele in Cdk13 gene. Embryonic lethality of Cdk13-deficient animals was observed by the embryonic day (E) 16.5, while live embryos were observed on E15.5. At this stage, improper development of multiple organs has been documented, partly resembling defects observed in patients with mutated CDK13. In particular, overall developmental delay, incomplete secondary palate formation with variability in severity among Cdk13-deficient animals or complete midline deficiency, kidney failure accompanied by congenital heart defects were detected. Based on further analyses, the lethality at this stage is a result of heart failure most likely due to multiple heart defects followed by insufficient blood circulation resulting in multiple organs dysfunctions. Thus, Cdk13 KO mice might be a very useful model for further studies focused on delineating signaling circuits and molecular mechanisms underlying CHDFIDD caused by mutation in CDK13 gene.
ABSTRACT
Multiple myeloma, which ranks as the second most common hematological malignancy, is known for its great genetic heterogeneity. One pathway, however, stands out in this diverse group. NF-κB pathway is one of the most important pathways in multiple myeloma not only for its role in pathogenesis, but also for its importance in various treatment strategies. Mutations in several major components of the NF-κB pathway and its regulators are present in at least 17% of primary multiple myeloma tumors and 42% of multiple myeloma cell lines. The NF-κB pathway regulates numerous genes, which influence development and pathogenesis of multiple myeloma. This significance of NF-κB for myeloma cells, however, is used against them, as current treatment strategies often use NF-κB as their primary or secondary target.
Subject(s)
Multiple Myeloma/etiology , Multiple Myeloma/metabolism , NF-kappa B/metabolism , Signal Transduction , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bone Marrow/drug effects , Bone Marrow/metabolism , Bone Marrow/pathology , Disease Management , Enzyme Activation , Humans , Molecular Targeted Therapy , Multiple Myeloma/diagnosis , Multiple Myeloma/therapy , NF-kappa B/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
Although tumor cells are the most reliable source of tumor DNA, biopsy of the tumor is an invasive procedure that should be avoided in some cases. The main limitation of any biopsy is sampling of one tumor site, which may not represent all malignant clones due to the heterogeneity of the tumor. These clones respond to treatment differently and thus directly influence survival of the patient. Circulating cell-free DNA (cfDNA) is released from multiple tumor sites, reflects overall heterogeneity of the tumor, and correlates with its progression. Detection of tumor-specific genetic and epigenetic aberrations in cfDNA could have a direct impact on molecular diagnosis, prognosis, follow-up of disease, monitoring of minimal residual disease, and response to treatment. While most cfDNA data are still experimental, they are very promising. This review focuses on cfDNA in hematological malignancies.
