microRNA, immunophenotypic, and somatic alterations in hematologic malignancies

Clinical Center

Investigators

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Abstract

After the completion of our major miRNA GATA2 project in 2020-2021, which was published in the Journal of Leukocyte Biology (PMID 34270823), we shifted focus on the second objective studying the somatic mutations, disease progression, and bone marrow pathology in GATA2 Deficiency and RUNX1 Familial Platelet Disorder. Project activities are listed below. 1. Somatic mutation analysis of myeloid neoplasms and marrow failure in GATA2 deficiency. During the past year we designed a new custom NGS panel with additional genes implicated in myeloid neoplasia that will be used for assaying bone marrow specimens from GATA2 patients. The NGS panel is being used to assay for acquired mutations from serial bone marrow specimens in order to detect molecular evidence of disease progression. These data are correlated with bone marrow morphology, immunophenotypic data from flow cytometry, cytogenetics and pathologic diagnosis. This study is ongoing. 2. Spectrum of pathologic findings and clonal evolution in RUNX1 familial platelet disorder with propensity for myeloid malignancy The RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM) is a rare autosomal dominant cancer predisposition syndrome. The lifetime risk of developing hematopoietic malignancies (HM) is 3040%, often MDS/AML. Understanding the baseline spectrum of bone marrow morphologic and genetic findings as well as temporal disease progression is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of HM. During the past year we analyzed the bone marrow pathology and correlated with clinicopathologic and NGS findings of pediatric patients to determine what percentage met criteria for refractory cytopenia of childhood based on current diagnostic criteria. An abstract was submitted to the American Society of Hematology annual meeting with the findings. 3. Pilot study of transcriptomic analysis of dysmegakaryopoiesis in GATA2 deficiency. We previously performed a pilot study to evaluate the ability to transcriptionally profile abnormal megakaryocytes in bone marrow core biopsies in MDS in GATA2 deficiency in comparison with normal megakaryocytes in the marrow of healthy individuals. This was done using digital spatial profiling technology to assay the expression of over 18,000 genes in megakaryocytes selected by morphology and expression of CD61. The pilot study was successful demonstrating significant differential expression of over 100 genes in dysplastic megakaryocytes vs. normal megakaroyocytes. This year we performed ELISAs on peripheral blood samples (GATA2 vs Healthy Control plasma) to assay for a subset of proteins that were aberrantly expressed based on the DSP studies. A larger study is planned for next year to confirm initial findings. 4. Several detailed invited review articles on germline predisposition to myeloid neoplasia and GATA2 deficiency were written during the past year based on clinical work and research emerging from this project. I also participated as a pathology chair in the International Consensus Classification for Myeloid Neoplasms contributing to new diagnostic guidelines for pathologists and clinicians. I contributed to other collaborative research projects with colleagues on multiple bone marrow diseases including VEXAS, aplastic anemia, DADA2, and other diseases.