Clonal Hematopoiesis in Patients with Severe Congenital Neutropenia

Severe congenital neutropenia (CN) is a pre-leukemia bone marrow failure syndrome presented with profound neutropenia early after birth due to markedly diminished granulocytic differentiation in bone marrow. Establishment of molecular genetic approach for detection of clonal hematopoiesis in blood or bone marrow of CN patients can assist in early recognition of leukemogenic transformation before clinical MDS/AML symptoms appear.

We established sequencing panel of 31 genes and 1696 “hot-spot” regions in genes recurrently mutated in MDS/AML. Using highly sensitive sequencing approach with implementation of Unique Molecular Identifiers (UMIs) we were able to characterize clonal hematopoiesis in CN patients at neutropenia stage (n=148), mutation burden in CN patients prior to AML/MDS (n=23), and at overt leukemia (n=18). We found that in CN/AML phase high frequency of RUNX1 and CSF3R mutations is usually accompanied by presence of specific leukemia associated genetic lesions. We also observed that presence of additional somatic mutations along with CSF3R mutations at neutropenia stage might be a strong indicator of advanced pre-leukemia phase and requires closer patient follow up.

Publication History

Article published online:
17 May 2022