Unravelling the ontogeny of clonal hematopoiesis and functional consequences in the stem cell compartment
Final Report Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) – defined by the presence of a somatic hematologic-cancer-associated gene mutation – occurs in the peripheral blood of at least 10% of persons older than 55 years of age without any history of hematologic neoplasm. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality. At present, caution is needed when predicting clinical consequences from a cancer-associated gene mutation in healthy persons. We unraveled novel insights into the complexity of effects mediated by CHIP. In a series of molecular studies we further characterized CHIP by elucidating its cellular origins and repartition within the hematopoietic differentiation tree, its role in healthy stem cell donors during allogeneic stem cell transplantation and its presence during complete remission of patients with acute myeloid leukemia harboring a translocation (8;21). We were able to prove that CHIP origins in Lin-CD34+CD38- hematopoietic stem cells with a subsequent differentiation shift towards the myeloid compartment. Mutant clones can harbor multiple clones but we also provided evidence that CHIP can be oligoclonal with different clones showing different dynamic and differentiation properties. In line with reports from other research groups pointing to a central of CHIP in inflammatory reactions, we showed for the first time that CHIP might foster the development of graft versus host disease in the setting of allogeneic hematopoietic stem transplantation (HSCT). This effect resulted in a reduced cumulative incidence of relapse in a large cohort of 500 HSSCT recipients. As our observation might have direct consequences for donor selection and clinical practice, confirmatory studies in even larger cohorts are now warranted. Additionally, we investigated how CHIP contributes to the clonal architecture of AML with t(8;21). As expected we showed that these mutations occur very early during leukemogenesis and are often followed by acquisition mutations affecting the RAS/RTK pathways. However, CHIP mutations often persist during complete remission, even in cases with no detectable t(8;21) fusion transcripts and contribute to clonal diversity observed at disease relapse. Our data suggest that mutations should be included in molecular follow-up analyses of patients with this distinct AML subtype. Collectively, the data show previously unappreciated results and open new avenues for diagnostic and therapeutic interventions. We were honored with the prestigious Curt-Meyer and DGHO Acute Leukemia Research awards.
Publications
- Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood. 2016 Dec 8;128(23):2666-2670
Mansouri L, Noerenberg D, Young E,…, Damm F.
(See online at https://doi.org/10.1182/blood-2016-03-704528) - EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia. 2017 Jul;31(7):1547-1554
Young E, Noerenberg D, Mansouri L,…, Damm F
(See online at https://doi.org/10.1038/leu.2016.359) - Hematopoietic lineage repartition and dynamic evolution of clonal hematopoiesis. Leukemia. 2018 Sep;32(9):1908-1919
Arends CM, Galan-Sousa J, Hoyer K, …, Damm F
(See online at https://doi.org/10.1038/s41375-018-0047-7) - Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019 Mar 7;133(10):1140-1151
Christen F, Hoyer K, Yoshida K, …, Damm F
(See online at https://doi.org/10.1182/blood-2018-05-852822) - The role of donor clonal hematopoiesis in allogeneic hematopoietic stem cell transplantation. J Clin Oncol. 2019 Feb 10;37(5):375-385
Frick M, Chan W, Arends CM, …, Damm F
(See online at https://doi.org/10.1200/JCO.2018.79.2184)
