Syndromic thrombocytopenia and predisposition to acute myelogenous leukemia caused by constitutional microdeletions on chromosome 21q.

Several lines of evidence support the presence of dosage-sensitive genes on chromosome 21 that regulate leukemogenesis and hematopoiesis. We report a detailed clinical and molecular characterization of 3 patients with chronic thrombocytopenia caused by distinct constitutional microdeletions involving chromosomal region 21q22.12. The patients exhibited growth restriction, dysmorphic features, and developmental delays. One patient developed acute myelogenous leukemia (AML) at 6 years of age. All 3 deletions included the RUNX1, CLIC6, DSCR, and KCNE1 genes. Our data provide additional support for the role of RUNX1 haploinsufficiency in megakaryopoiesis and predisposition to AML. The leukemic clone had trisomy 21 resulting from duplication of chromosome 21 containing the RUNX1 deletion. This shows that genes other than RUNX1 must also play a role in AML associated with trisomy 21. We recommend that children with syndromic thrombocytopenia have clinical array-comparative genomic hybridization analysis and appropriate cytogenetic studies to facilitate our ability to provide a definitive diagnosis.

Overexpression of ZNF342 by juxtaposition with MPO promoter/enhancer in the novel translocation t(17;19)(q23;q13.32) in pediatric acute myeloid leukemia and analysis of ZNF342 expression in leukemia.

We report a novel translocation t(17;19)(q22;q13.32) found in 100% of blast cells from a pediatric acute myeloid leukemia (AML) patient. Fluorescence in situ hybridization and vectorette polymerase chain reaction were used to precisely map the chromosomal breakpoint located on the derivative chromosome 17 at 352 bp 5' of MPO, encoding myeloperoxidase a highly expressed protein in myeloid cells, and 2,085 bp 5' of ZNF342 on 19q, encoding a transcription factor expressed in human stem cells and previously implicated in mouse models of leukemia. Analysis of RNA levels from the patient sample revealed significant overexpression of ZNF342, potentially contributing to AML formation. This is the first report of a translocation in myeloid leukemia occurring only in the promoter/enhancer regions of the two genes involved, similar to translocations commonly found in lymphoid malignancies. Analysis of ZNF342 protein levels in a large dataset of leukemia samples by reverse phase protein array showed that higher levels of ZNF342 expression in acute lymphoblastic leukemia was associated with poorer outcome (P = 0.033). In the myeloid leukemia samples with the highest ZNF342 expression, there was overrepresentation of FLT3 internal tandem duplication (P = 0.0016) and AML subtype M7 (P = 0.0002). Thus, overexpression of ZNF342 by translocation or other mechanisms contributes to leukemia biology in multiple hematopoietic compartments.

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.