Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances

Abstract

Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.

Graphical abstract

Figure 1.

Defective ribosome subunit joining in SDS. The top panel shows a normal ribosome subunit joining that occurs after eviction of eIF6 by SBDS and EFL1. The bottom panel shows an impaired ribosome joining defect in SDS due to the inability to displace eIF6 from the 60S intersubunit surface.

Figure 2.

Pathways of somatic clonal evolution in SDS. Somatic blood mutations in TP53 (red) and EIF6 (green) are recurrent in patients with SDS and confer a selective advantage to HSC via distinct mechanisms. Inactivating EIF6 mutations relieve the fitness defect caused by SBDS deficiency by improving ribosome joining and translation efficiency. In contrast, heterozygous TP53 mutations improve HSC fitness by decreasing the cell checkpoint activation (eg, p21) but do not improve the underlying ribosome joining defect. Acquisition of a second TP53 mutation (ie, biallelic TP53-mutated clone) results in the complete loss of cellular checkpoints, genomic instability, and eventual progression to a myeloid malignancy.

Figure 3.

Clonal dynamics of somatic mutations in SDS. (A) Representative example of clinical NGS in a patient with SDS undergoing serial bone marrow examinations. TP53- and EIF6-mutated clones are colored red and green, respectively. Solid red line corresponds to the biallelic TP53 clone that eventually progresses to MDS. Light-blue bar highlights year 3 of bone marrow surveillance. (B) scDNA-seq at year 3 of surveillance. Each row represents a unique EIF6- and TP53-mutated clones with VAF as a percentage below. Each dot corresponds to a single cell belonging to a given clone. Heterozygous mutations have a VAF of ∼0.5. The TP53 mutation in clone 3 has a VAF of ∼1.0, indicating biallelic TP53 mutation. The biallelic TP53-mutated clone expands exponentially and represents the dominant clone at the time of MDS diagnosis. This scenario demonstrates the ability of scDNA-seq to reveal the clonal hierarchy of somatic mutations and identify high-risk TP53 mutations years before the clinical diagnosis of a myeloid malignancy. In addition, we provide a specific clinical example in the text describing a patient with SDS who was found to have a detectable biallelic TP53-mutated clone using scDNA-seq that eventually gave rise to leukemia despite no other concerning clinicopathologic or cytogenetic features during routine surveillance of bone marrow and blood counts a few months preceeding leukemia diagnosis.