Somatic mutations and clonal hematopoiesis in congenital neutropenia

Jun Xia, Christopher A. Miller, Jack Baty, Amrita Ramesh, Matthew R.M. Jotte, Robert S. Fulton, Tiphanie P. Vogel, Megan A. Cooper, Kelly J. Walkovich, Vahagn Makaryan, Audrey A. Bolyard, Mary C. Dinauer, David B. Wilson, Adrianna Vlachos, Kasiani C. Myers, Robert J. Rothbaum, Alison A. Bertuch, David C. Dale, Akiko Shimamura, Laurence A. Boxer and Daniel C. Link

Key points

  • Hematopoietic stem/progenitor mutation burden is not increased in severe congenital neutropenia

  • Clonal hematopoiesis due to mutations of TP53 are present in the majority of patients with Shwachman Diamond syndrome


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.

  • Submitted August 14, 2017.
  • Accepted October 21, 2017.