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Multidisciplinary characterization of rare MPL Y591 and R592 variants in myeloid disorders: from clinical correlation
Alessandro Laganà1, Giovanni Iaquinta2, Michelina Santopietro3
1Hematology, Department of Translational and Precision Medicine, Policlinico Umberto I-Sapienza University, Rome, Italy.
Experimental Hematology
|July 3, 2026
Summary
Rare MPL gene variants (Y591, R592) in myeloid neoplasms are not primary drivers but may modify disease. These uncommon mutations, including MPL p.Y591D/H and p.R592Q, can influence MPN phenotypes and treatment responses.
Area of Science:
- Hematology
- Molecular Biology
- Genetics
Background:
- Somatic mutations in the thrombopoietin receptor gene (MPL) exon 10 are known drivers of myeloproliferative neoplasms (MPNs).
- The clinical significance of rare, atypical MPL variants remains largely undetermined.
- MPL variants affecting residues Y591 and R592 represent such uncommon alterations.
Purpose of the Study:
- To investigate the clinical relevance and pathogenicity of three uncommon MPL variants: p.Y591D, p.Y591H, and p.R592Q.
- To integrate clinical data with in silico predictions and structural modeling to assess variant impact.
- To clarify the role of these variants in myeloid neoplasms.
Main Methods:
- Retrospective analysis of a multicenter cohort of myeloid neoplasm patients undergoing next-generation sequencing (NGS).
- Integration of clinical data, literature review, in silico pathogenicity prediction tools.
- Structural bioinformatics modeling of the MPL-JAK2 complex.
Main Results:
- Eight patients with MPL p.Y591D, p.Y591H, or p.R592Q variants were identified across diverse myeloid disorders.
- These variants frequently co-occurred with canonical MPN driver mutations.
- Y591 substitutions were associated with aggressive phenotypes and potential resistance to JAK-inhibitors, while R592Q showed variable outcomes.
- Structural modeling suggested minor local rearrangements but no significant disruption of the MPL-JAK2 complex.
- Y591 variants may disrupt regulatory motifs, potentially increasing receptor sensitivity to thrombopoietin.
Conclusions:
- MPL p.R592Q is a variant of uncertain significance (VUS).
- MPL p.Y591D and p.Y591H may be classified as VUS or likely oncogenic, depending on the framework.
- These uncommon MPL variants (p.Y591D/H, p.R592Q) are unlikely to be primary oncogenic drivers but may function as disease modifiers in myeloid neoplasms.
