SRP72 – Acute Myeloid Leukemia

SRP72 is increasingly recognized as a gene associated with predisposition to myeloid malignancies, including acute myeloid leukemia. Studies have implicated SRP72 in familial cases where patients present features consistent with hematopoietic dysfunction. In the context of acute myeloid leukemia, the gene is one of several that have been evaluated for its role in inherited susceptibility, underscoring the need for its consideration in diagnostic panels (PMID:27248996). The clinical presentation in affected individuals typically involves a hematological phenotype with cytopenias and dysplastic bone marrow findings. The evolving evidence highlights the relevance of SRP72 in the differential diagnosis of familial blood disorders. This summary integrates multiple lines of evidence to support its association with acute myeloid leukemia.

Multi‐patient studies have reported clustering of myeloid malignancies in families with a history of acute myeloid leukemia and related disorders. One study reviewed familial predispositions to myelodysplastic syndrome and acute myeloid leukemia, including cases with SRP72 involvement (PMID:27248996). A separate investigation from Hungary described three families with a total of nine affected individuals in pedigrees of acute myeloid leukemia and myelodysplasia; although SRP72 mutations were not identified in that cohort, the gene remains under consideration due to its prior association with similar phenotypes (PMID:28357685). These studies collectively suggest a notable, albeit complex, genetic contribution from SRP72.

The genetic evidence supports an autosomal dominant inheritance pattern for SRP72-related disorders. Reports indicate that segregation analysis in available families has demonstrated that the presence of deleterious variants tracks with the disease phenotype, although the number of affected relatives is limited to a small number of familial clusters. Specifically, the clustering in three pedigrees with nine affected individuals provides a moderate level of genetic support (PMID:28357685). The overall genetic findings are bolstered by the observation of discrete coding variants identified through targeted sequencing approaches.

A key reported variant is c.620G>A (p.Arg207His), which has been identified in individuals with a clinical presentation overlapping bone marrow failure and myeloid malignancies. This missense change, affecting a conserved residue, underscores the pathogenic potential through disruption of protein function. While additional variant classes have been described in SRP72, the recurrent identification of this variant highlights its diagnostic relevance. The variant provides a molecular marker that, when observed together with clinical findings, can help guide genetic counseling and risk assessment in affected families (PMID:22541560).

Functional studies have been instrumental in elucidating the role of SRP72 in disease. Experimental assays demonstrated that the c.620G>A (p.Arg207His) variant impairs proper localization of SRP72 within the cell and disrupts the assembly of the signal recognition particle complex. These defects are consistent with a dominant-negative mechanism, ultimately leading to aberrant protein trafficking and hematopoietic dysfunction. The functional concordance with the observed clinical phenotype reinforces the gene’s role in the pathogenesis of acute myeloid leukemia (PMID:22541560).

In summary, the integration of genetic and functional data supports a strong association between SRP72 and acute myeloid leukemia. Although there is some conflicting evidence from mutation screening in certain family cohorts, the overall pattern of autosomal dominant inheritance, the segregation of rare deleterious variants, and corroborative in vitro functional studies lend substantial support for the clinical relevance of SRP72 in leukemogenesis. This evidence not only advances our understanding of the molecular underpinnings of familial myeloid malignancies but also provides a valuable marker for diagnostic decision‑making and clinical management.

References

• International journal of molecular sciences • 2016 • Hereditary Predispositions to Myelodysplastic Syndrome PMID:27248996
• Pathology oncology research • 2018 • Familial Acute Myeloid Leukemia and Myelodysplasia in Hungary PMID:28357685
• American journal of human genetics • 2012 • Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia PMID:22541560

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