Hematologic indices in individuals with pathogenic germline DICER1 variants

Abstract

Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at www.clinicaltrials.gov as #NCT01247597.

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

“…Interestingly, when the deletion of Dicer1 was induced in mature osteolineage cells through the use of the osteocalcin promoter, no malignancy was observed, demonstrating that the 'cell type specificity' in the genetic lesion is essential [85]. However, the role of DICER1 in the MDS pathophysiology has recently been questioned by a report where no evidence was found between the germline DICER1 alterations and onset of MDS disease [86]. Studies have reported reduced expression of DICER1 in MDS MSC [85,87]; therefore, further studies are needed to study the role of DICER1 in MDS disease.…”

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Culturing normal HSPCs with MSCs from these mutant mice resulted in altered hematopoietic cell function and morphology, while normal hematopoiesis ensued after the transplantation of bone marrow HSPCs from the mutant mice into wild-type murine recipients [ 280 ]. In contrast to these murine studies, recent research on the initiation of MDS in humans was not found to be associated with pathogenic germline DICER1 variants [ 281 , 282 ]. Studies by Balderman et al [ 283 ], using a transgenic murine MDS model, further support the concept of an altered bone marrow microenvironment contributing to myeloid skewing during MDS progression.…”

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

“…Consistent with these findings, reduced expression of Dicer1 mRNA and protein levels as well down-regulated Sbds gene expression were also reported in BM-MSCs from MDS patients ( 57 ). On the other hand, a recent study showed that none out of 121 individuals with germline pathogenic Dicer1 variants developed MDS or leukemia ( 58 ). Thus, the clinical significance of Dicer1 in the MDS setting remains elusive.…”