Tracing the development of acute myeloid leukemia in 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.

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy

“…In both cases, sucking and swallowing difficulties, frequently observed in context of orofacial dyspraxia following stroke involving insular regions, hypotonia, mild motor and speech delay, were attributed to ancient strokes in MCA territories that were seen on initial MRI. Other signs such as transitory coagulation defects without bleeding tendency in trio 1 proband—coagulation defects were reported so far in one CBL- mutated patient27—and café-au-lait spots in trio 3 proband were subtle and did not lead neuropaediatricians to consider a diagnosis of RASopathy. Indeed, no ‘red flag’ suggestive of a RASopathy has been identified by neuropaediatricians in both girls, in whom MMA was the hallmark manifestation at diagnosis.…”

Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia

“…4,6 Investigation of the mechanisms underlying the disease progression has identified genetic alterations, such as mutations in the Asxl1 (additional sex combslike 1), Setbp1 (SET-binding protein 1), and NPM1 (nucleophosmin) genes [43][44][45][46] ; however, little is known about genes whose expressional changes are responsible for disease evolution. By employing retrovirusmediated mutagenesis, we identified Evi1, a gene encoding a transcription factor involved in normal hematopoiesis and leukemogenesis, 28 as a cooperative gene with Cbl Q367P and demonstrated that overexpressed EVI1 synergized with CBL Q367P to develop AML.…”

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

“…Several recent studies have identified CBL mutations in 5 –10 % of CBF-AML 5–9 . CBL is also frequently mutated in myelodysplastic/myeloproliferative neoplasms, but rarely mutated in other types of de novo AML 10–18 .…”