Tracing the development of acute myeloid leukemia in CBL syndrome
Heiko Becker1, Kenichi Yoshida, Nadja Blagitko-Dorfs
1Department of Medicine I, Medical Center-University of Freiburg, Freiburg, Germany;
Insights
Adults with CBL syndrome can develop acute myeloid leukemia (AML). This study details a case where a CBL mutation became homozygous, leading to AML and subsequent stable hematopoiesis with the mutation.
Area of Science:
- Hematology
- Oncology
- Human Genetics
Background:
- CBL syndrome is a rare genetic disorder associated with an increased risk of hematologic malignancies.
- Germline mutations in CBL can predispose individuals to myeloid leukemias.
Observation:
- An adult with CBL syndrome, due to a de novo germline CBL mutation (D390), developed acute myeloid leukemia (AML).
- The AML bone marrow exhibited homozygous CBL mutation via copy-neutral loss-of-heterozygosity and chromosomal gain, alongside an inv(16)(p13q22) and 12 additional gene mutations.
Findings:
- Complete remission of AML was achieved, yet hematopoiesis stably maintained the homozygous CBL mutation.
- No new mutations were detected in granulocytes during remission, suggesting the homozygous CBL mutation is compatible with stable, albeit aberrant, hematopoiesis.
Implications:
- This case highlights a potential pathway for AML development in adults with CBL syndrome.
- It suggests that genetically aberrant hematopoiesis can persist asymptomatically, underscoring the importance of genetic surveillance in individuals with CBL syndrome.
Abstract:
We describe the development of acute myeloid leukemia (AML) in an adult with CBL syndrome caused by a heterozygous de novo germline mutation in CBL codon D390. In the AML bone marrow, the mutated CBL allele was homozygous after copy number-neutral loss-of-heterozygosity and amplified through a chromosomal gain; moreover, an inv(16)(p13q22) and, as assessed by whole-exome sequencing, 12 gene mutations (eg, in CAND1, NID2, PTPRT, DOCK6) were additionally acquired. During complete remission of the AML, in the presence of normal blood counts, the hematopoiesis stably maintained the homozygous CBL mutation, which is reminiscent of the situation in children with CBL syndrome and transient juvenile myelomonocytic leukemia. No additional mutations were identified by whole-exome sequencing in granulocytes during complete remission. The study highlights the development of AML in an adult with CBL syndrome and, more generally, in genetically aberrant but clinically inconspicuous hematopoiesis.
