Setting Of Myelodysplastic Syndrome Research Articles

A Specific Mesenchymal Stem and Progenitor Cell (MSPC) Subpopulation with a Multi-Potent Gene Signature Is Transcriptionally Altered in the Setting of Myelodysplastic Syndrome (MDS) in Primary Human Bone Marrow Aspirates

Introduction: Myelodysplastic syndromes (MDS) are genetically diverse and heterogeneous diseases characterized by dysplasia and cytopenias and a dismal prognosis of ˂ 50% overall survival at 5-years. In vitro and in vivo experimental data have shown that the bone marrow microenvironment (BMME) may play a role in disease progression and, importantly, in murine models, transplantation of MDS to a healthy BMME was shown to mitigate disease. Mesenchymal Stem and Progenitor Cells (MSPCs), as part of the BMME, give rise to multiple non-hematopoietic progenitor cells and provide essential support to hematopoietic stem cells. MSPCs have also been shown to be functionally altered in patients with myeloid neoplasias. Murine studies have demonstrated distinct roles for specific subsets of bone marrow mesenchymal cells in myeloid malignancies. We hypothesized that specific subsets of human bone marrow MSPCs will play differential roles in the pathogenesis of MDS. Using flow-cytometry, high-throughput sequencing and gene set enrichment analysis (GSEA), we characterized human MSPCs in the bone marrow aspirates from patients with MDS and normal healthy controls (NBM). Methods: Mononuclear cells were isolated by iliac crest bone marrow aspiration from 10-healthy donors and 14-patients at the University of Rochester Medical Center. Within the non-hematopoietic (CD45-, CD235-), non-endothelial (CD31-) bone marrow compartment, we enriched and isolated 3 distinct-subpopulations of MSPCs based on cell-surface expression of CD271/NGFR, CD106/VCAM-1 and CD146/MCAM. Populations were defined as follows: CD271+/CD146- (CD271+), CD271+/CD146+/CD106+ (DPCD106+), and CD271+/CD146+/CD106- (DPCD106-). RNA-seq analysis was performed on each subpopulation to define transcriptional signatures (TS) and gene set enrichment patterns. Statistically significant differentially expressed genes (DEGs) were defined by fold-change ≥ ±1 and p-value ˂0.05. Results: We first set out to define differences in the TS and interrogate the function of MSPC populations in NBM. Principle component analysis (PCA) demonstrated the highest variance between the DPCD106+ and the CD271+ populations. The number of DEGs were also highest between the DPCD106+ and CD271+ populations (n=3,619 genes). GSEA identified 745 and 336 gene sets with positive enrichment in the DPCD106+ and CD271+ group, respectively, and illustrated that the DPCD106+ population was significantly enriched in gene sets involved in early embryonic developmental and "stem-like" pathways whereas the CD271+ population was enriched in cell cycling, DNA and chromosomal organization. In the setting of MDS, the mean relative frequency of MDS CD271+ nearly tripled (0.4230/0.1445; p-value 0.045). Compared to NBM, MDS DPCD106+ cells had the highest variance by PCA and the highest number of DEGs (n=560). GSEA identified 19-gene sets with significant enrichment in the MDS DPCD106+ group and, intriguingly, 12 (63%) were identical to gene sets enriched in the CD271+ group. Furthermore, of the 560 DEGs in the MDS DPCD106+ MSPCs, 300 were upregulated and, of those, 160 (53%) were identical to upregulated genes in the CD271+ NBM group including the acquisition of a proliferative signature. Altogether, this data suggests a switch in the TS of theDPCD106+ population in the setting of MDS. Importantly, this TS clustered MDS DPCD106+ from NBM, regardless of MDS risk category. Conclusion: We successfully characterized 3 subtypes of MSPCs in NBM and MDS. In NBM, we demonstrate that cell surface expression of CD271, CD146 and CD106 defined the most stem-like TS within the non-hematopoietic, non-endothelial bone marrow compartment. In the setting of MDS, the increase in population frequency of the CD271+ cells and the concomitant transcriptomic aberrations observed in the MDS derived DPCD106+ population support the hypothesis that specific MSPC populations have differential roles in MDS pathogenesis. Further, we identify a TS that discriminates MDS derived MSPCs from NBM irrespective of MDS-risk category. This suggests that alterations within specific MSPC populations may represent a unifying pathway in disease pathogenesis despite heterogeneity and genetic drivers intrinsic to the MDS clone. Thus, targeting the BMME represents a potentially novel therapeutic strategy aimed at mitigating disease and restoring normal hematopoiesis in patients with MDS. Disclosures Liesveld: Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Scadden:Editas Medicine: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bone Therapeutics: Consultancy; Clear Creek Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Sponsored research; Fate Therapeutics: Consultancy, Equity Ownership; Red Oak Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fog Pharma: Consultancy; Agios Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; LifeVaultBio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

The role of T2*-weighted gradient echo in the diagnosis of tumefactive intrahepatic extramedullary hematopoiesis in myelodysplastic syndrome and diffuse hepatic iron overload: a case report and review of the literature

BackgroundExtramedullary hematopoiesis is the proliferation of hematopoietic cells outside bone marrow secondary to marrow hematopoiesis failure. Extramedullary hematopoiesis rarely presents as a mass-forming hepatic lesion; in this case, imaging-based differentiation from primary and metastatic hepatic neoplasms is difficult, often leading to biopsy for definitive diagnosis. We report a case of tumefactive hepatic extramedullary hematopoiesis in the setting of myelodysplastic syndrome with concurrent hepatic iron overload, and the role of T2*-weighted gradient-echo magnetic resonance imaging in differentiating extramedullary hematopoiesis from primary and metastatic hepatic lesions. To the best of our knowledge, T2*-weighted gradient-echo evaluation of extramedullary hematopoiesis in the setting of diffuse hepatic hemochromatosis has not been previously described.Case presentationA 52-year-old white man with myelodysplastic syndrome and marrow fibrosis was found to have a 4 cm hepatic lesion on ultrasound during workup for bone marrow transplantation. Magnetic resonance imaging revealed diffuse hepatic iron overload and non-visualization of the lesion on T2* gradient-echo sequence suggesting the presence of iron deposition within the lesion similar to that in background hepatic parenchyma. Subsequent ultrasound-guided biopsy of the lesion revealed extramedullary hematopoiesis. Six months later, while still being evaluated for bone marrow transplant, our patient was found to have poor pulmonary function tests. Follow-up computed tomography angiogram showed a mass within his right main pulmonary artery. Bronchoscopic biopsy of this mass once again revealed extramedullary hematopoiesis. He received radiation therapy to his chest. However, 2 weeks later, he developed mediastinal hematoma and died shortly afterward, secondary to respiratory arrest.ConclusionsMass-forming extramedullary hematopoiesis is rare; however, our report emphasizes that it needs to be considered in the initial differential diagnosis of hepatic lesions arising in the setting of bone marrow disorders. We also show that in the setting of diffuse hepatic iron overload, tumefactive extramedullary hematopoiesis appeared isointense to background liver on T2* gradient-echo sequence, while adenoma, hepatoma, and hepatic metastasis appear hyperintense. Thus, T2*-weighted gradient-echo sequence may have a potential role in the imaging diagnosis of mass-forming hepatic extramedullary hematopoiesis arising in the setting of diffuse iron overload.

Myeloid leukemia cutis in the setting of myelodysplastic syndrome: a crucial dermatological diagnosis

Cutaneous involvement by myeloid leukemic cells is an unusual phenomenon. Clinical manifestations vary from erythematous papules to plum-colored plaques and nodules that may become purpuric and ulcerate. The definitive diagnosis of myeloid leukemia cutis requires the analysis of biopsy specimens using immunohistochemical staining to determine the expression of selective cell surface markers. We will review myeloid leukemia when first evident in the skin, particularly in the setting of myelodysplastic syndrome. The diagnosis of leukemia cutis in patients with myelodysplastic syndrome is indicative of concomitant or impending acute leukemic transformation. The early recognition and accurate identification of leukemic skin infiltrates in myelodysplastic patients is crucial, as this finding can have significant therapeutic and prognostic implications.