Editors' ChoiceAPLASTIC ANEMIA

Clone wars

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Science Translational Medicine  15 Jul 2015:
Vol. 7, Issue 296, pp. 296ec119
DOI: 10.1126/scitranslmed.aac8560

Immune-mediated aplastic anemia is a life-threatening chronic illness. In the course of disease, renewal of the blood cells gradually slows down as self-reactive T lymphocytes kill hematopoietic stem cells, leaving a barren landscape of empty bone marrow behind. Although T cell immunosuppression may allow bone marrow recovery, many patients never respond to immune-modulating agents and require stem cell transplantation to survive. Worse, one in five patients will suffer from the dreaded “clonal evolution” (expansion of hematopoietic clones leading to leukemia) years after therapy. These high-risk individuals cannot be identified until overt leukemia occurs, which may be too late for curative treatment.

In their multi-institutional trial, Yoshizato et al. asked how many aplastic anemia patients develop clonal hematopoiesis when bone marrow cells proliferate under the continued T cell assault. The authors screened over 400 patients with a battery of DNA microarrays, analysis of bone marrow failure genes, and whole-exome sequencing. Combined, these methods identified clonal hematopoiesis in most patients, indicating that clonal evolution in aplastic anemia occurs commonly and earlier than anticipated. Patients with mutations of selected cancer-associated genes, such as the TP53 tumor suppressor or the leukemia-associated transcription factor RUNX1, had poor response to immunosuppression and inferior survival compared with individuals with “favorable” mutations. Further validation will determine whether these mutational signatures should guide the choice of risk-based therapies.

Most strikingly, samples obtained sequentially from individual patients showed that hematopoietic clones dynamically expand and disappear over years. In particularly informative cases, a small clone present at the diagnosis of aplastic anemia acquired further mutations and progressively dominated the bone marrow, evolving into leukemia. These observations illustrate how stepwise mutagenesis gradually generates cancer cells in vivo.

The bone marrow in aplastic anemia may appear deserted under the microscope, but the report by Yoshizato et al. revealed robust hematopoietic clone battles at submicroscopic resolution. In the future, early detection of the premalignant clones may allow immediate intervention and improved survival in aplastic anemia patients prone to developing leukemia.

T. Yoshizato et al., Somatic mutations and clonal hematopoiesis in aplastic anemia. N. Engl. J. Med. 373, 35–47 (2015). [Abstract]

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