Česká Genetická Banka

BLOOD: 28. 11. 2013

BLOOD: The biology and clinical impact of genetic lesions in myeloid malignancies

"A longstanding endeavor to define the genetic lesions that drive myeloid malignances has stimulated a period of remarkable discovery. Enabled by technological advances that have sharply decreased the cost of DNA sequencing, the full compendium of common, recurrent somatic mutations in the coding genome of myeloid malignancies is nearly complete. As the focus of genetic discovery shifts to the noncoding genome, renewed attention is being applied to the clinical and biological implications of recent genomic advances. Although the potential for this newfound knowledge to influence the care of patients has not yet been realized, broad genetic surveys of patient samples are now being used to improve the accuracy of disease diagnosis, define a molecular taxonomy of myeloid malignancies, refine prognostic and predictive models, and identify novel therapeutic strategies. Here, we will review recent advances in the genetics of myeloid malignancies and discuss their potential impact on clinical practice."

http://bloodjournal.hematologylibrary.org/content/122/23/3741.abstract

 

NATURE: Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness

"‘Pre-leukaemic’ mutations are thought to promote clonal expansion of haematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness¹; however, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative neoplasms and leukaemia². Here we show that a single allele of oncogenic Nras^G12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukaemia initiation. Nras^G12D also confers long-term self-renewal potential to multipotent progenitors. To explore the mechanism by which Nras^G12D promotes HSC proliferation and self-renewal, we assessed cell-cycle kinetics using H2B–GFP label retention and 5-bromodeoxyuridine (BrdU) incorporation. Nras^G12D had a bimodal effect on HSCs, increasing the frequency with which some HSCs divide and reducing the frequency with which others divide. This mirrored bimodal effects on reconstituting potential, as rarely dividing Nras^G12D HSCs outcompeted wild-type HSCs, whereas frequently dividing Nras^G12D HSCs did not. Nras^G12D caused these effects by promoting STAT5 signalling, inducing different transcriptional responses in different subsets of HSCs. One signal can therefore increase HSC proliferation, competitiveness and self-renewal through bimodal effects on HSC gene expression, cycling and reconstituting potential."

http://www.nature.com/nature/journal/v504/n7478/full/nature12830.html