About this Research Topic
Multiple Myeloma is characterized by a plethora of genetic alterations. Broadly, two pathogenetic pathways can be delineated: hyperdiploid myeloma, characterized by a gain of odd numbered choromosomes, and IgH-translocations, involving the heavy chain promotor. Besides this, single nucleotide variants are present in all patients, but no unifying mutation has been found. Most frequent aberrations include alterations of the ras/raf-pathway. Of these, BRAFV600E mutation, present in about 4% of previously untreated patients, is clinically actionable. Myeloma patients frequently show a variable number of subclones. Given this background, genetic instability is thought to be present in disease progression. As multiple myeloma as a rule relapses after successful chemotherapeutic treatment, genetic instability could likewise be thought to be involved in drug resistance. In turn, genetic instability could represent potential targets for novel treatment strategies, including aurora kinase, PARP, HDAC, telomerase or DNMT-inhibitors. Multiple myeloma has been intensively characterized at the molecular level, including work by the members of our application. At the same time, growing evidence exists that part of mutations observed in hematological malignancies are likewise found in age-increasing frequency in healthy individuals.
We will address the following questions:
i) What evidence exists for genetic instability driving progression from asymptomatic to symptomatic and relapsed myeloma?
ii) Is it driven by ongoing genetic alterations in malignant plasma cells?
iii) Is it driven by factors in the altering bone marrow microenvironment?
iv) What is the relation between ongoing genetic instability and clonal evolution?
v) Can clinical conclusions be drawn, e.g. aiming at earlier treatment when a less complex aberration pattern is present?
vi) What is the role of genetic instability in mechanisms of drug resistance?
vii) How and by which models is it best studied?
viii) How does this fit with the general pattern of accumulating genetic alterations in aging hematopoiesis?
Keywords: Genomic instability, DNA repair, Drug resistance, Multiple Myeloma, Clonal evolution
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