Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia

Abstract

c-CBL (CBL) encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by constitutional anomalies that include impaired growth, developmental delay, cryptorchidism, and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.Y371H mutant Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT, and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic, and functional consequences that are reminiscent of disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, and Noonan, Costello, cardiofaciocutaneous, and Legius syndromes.

CBL mutations in infant acute lymphoblastic leukaemia

“…These data suggested that CBL mutation may have a strong association with very early onset disease. CBL mutations have been reported as germline mutations in JMML (Niemeyer et al, 2010). Unfortunately, we could not investigate whether the mutations in our cases were germline mutations or not, because somatic cells were not available.…”

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

“…1A). This is especially advantageous because studies have shown that expression of wild type CBL can rescue or mask the effects of CBL mutants (23,40).…”

Childhood Myelodysplastic Syndrome: Focus on the Approach to Diagnosis and Treatment of Juvenile Myelomonocytic Leukemia

“…We and others have shown that defective E3 ligase activity results from specific substitutions at this region (Y371H, Y371S) only in the absence of the wild-type protein. 25,29 An initial review of the medical records of 21 children with JMML harboring these homozygous mutations revealed that a number of them also shared other phenotypic features, suggesting that these lesions might first occur as germ-line events. Indeed, further investigation of the germ-line tissues from 17 of these patients revealed heterozygous lesions, and additional studies of parental DNA, when available, indicated that these mutations are autosomally inherited in a dominant fashion approximately 50% of the time, while they arise spontaneously in the other 50%.…”