Somatic mutations and clonal hematopoiesis in congenital neutropenia.

Blood. 2017 Nov 1. pii: blood-2017-08-801985. doi: 10.1182/blood-2017-08-801985. [Epub ahead of print]


Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome were identified in HSPCs from patients with SCN compared to 3.9 ± 0.4 for healthy controls (p=NS). Clonal hematopoiesis due to mutations in TP53 were present in 48% (13/27) of patients with SDS but were not seen in healthy controls (0/17, p<0.001) or patients with SCN (0/40, p<0.001). Our SDS cohort was young (median age 6.3 years) and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R were present in patients with SCN but were not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including G-CSF, does not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to MDS/AML in patients with SDS.


Xia J, Miller CA, Baty J, Ramesh A, Jotte MRM, Fulton RS, Vogel TP, Cooper MA, Walkovich KJ, Makaryan V, Bolyard AA, Dinauer MC, Wilson DB, Vlachos A, Myers KC, Rothbaum RJ, Bertuch AA, Dale DC, Shimamura A, Boxer LA, Link DC

Institute Authors

Chris Miller, Ph.D., Robert Fulton