Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation.

Abstract

A subset of patients with familial platelet disorder with propensity to myeloid malignancy and germline RUNX1 mutation develops hematological malignancies, often myelodysplastic syndrome/acute myeloid leukemia, currently recognized in the 2016 WHO classification. Patients who develop hematologic malignancies are typically young, respond poorly to conventional therapy, and need allogeneic stem cell transplant from non-familial donors. Understanding the spectrum of bone marrow morphologic and genetic findings in these patients is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of hematologic malignancies, particularly myelodysplastic syndrome. However, bone marrow features remain poorly characterized. To address this knowledge gap, we analyzed the clinicopathologic and genetic findings of 11 patients from 7 pedigrees. Of these, 6 patients did not develop hematologic malignancies over a 22-month follow-up period; 5 patients developed hematologic malignancies (3 acute myeloid leukemia; 2 myelodysplastic syndrome). All patients had thrombocytopenia at initial presentation. All 6 patients who did not develop hematologic malignancies showed baseline bone marrow abnormalities: low-for-age cellularity (n=4), dysmegakaryopoiesis (n=5), megakaryocytic hypoplasia/hyperplasia (n=5), and eosinophilia (n=4). Two patients had multiple immunophenotypic alterations in CD34-positive myeloblasts; 1 patient had clonal hematopoiesis. In contrast, patients who developed hematologic malignancies had additional cytopenia(s) (n=4), abnormal platelet granulation (n=5), bone marrow hypercellularity (n=4), dysplasia in ≥2 lineages including megakaryocytes (n=3) and acquired clonal genetic aberrations (n=5). In conclusion, our study demonstrated that specific bone marrow abnormalities and acquired genetic alterations may be harbingers of progression to hematological malignancies in patients with familial platelet disorder with germline RUNX1 mutation.

• Authors: Rashmi Kanagal-Shamanna, Sanam Loghavi, Courtney D DiNardo, L Jeffrey Medeiros, Guillermo Garcia-Manero, Elias Jabbour, Mark J Routbort, Rajyalakshmi Luthra, Carlos E Bueso-Ramos, Joseph D Khoury
• Journal: Haematologica (Haematologica) Vol. 102 Issue 10 Pg. 1661-1670 (10 2017) ISSN: 1592-8721 [Electronic] Italy
• PMID: 28659335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright© 2017 Ferrata Storti Foundation.

Chemical References

• Core Binding Factor Alpha 2 Subunit

Topics

• Biopsy
• Blood Platelet Disorders (complications, genetics, pathology)
• Bone Marrow (pathology)
• Clonal Evolution
• Core Binding Factor Alpha 2 Subunit (genetics)
• DNA Mutational Analysis
• Disease Progression
• Disease Susceptibility
• Family
• Female
• Follow-Up Studies
• Germ-Line Mutation
• Humans
• Immunophenotyping
• Karyotyping
• Male
• Myeloproliferative Disorders (diagnosis, etiology)
• Pedigree