ABSTRACT
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.
Subject(s)
Benzamides/pharmacology , Enhancer Elements, Genetic , Enzyme Inhibitors/pharmacology , Histone Demethylases/antagonists & inhibitors , Leukemia/pathology , Myelodysplastic Syndromes/complications , Animals , Cell Division/drug effects , Cell Line, Tumor , Humans , Karyotyping , Leukemia/etiology , Leukemia/genetics , Mice , Mice, Inbred NODABSTRACT
A 16-year-old girl with refractory acute lymphoblastic leukemia underwent reduced-intensity hematopoietic stem cell transplantation from her two-locus-mismatched haploidentical mother, who was microchimeric for the patient's hematopoietic cells. The conditioning regimen comprised melphalan, fludarabine, and low-dose total body irradiation. Non-T-cell-depleted peripheral blood stem cells were infused with graft-versus-host disease (GVHD) prophylaxis consisting of tacrolimus, prednisolone, and short-course methotrexate. Complete donor-type engraftment without evidence of residual leukemia was confirmed on day 22. Severe GVHD was not observed despite rapid cessation of immunosuppression. The patient remains well in continuous remission 15 months after transplant. This successful experience suggests that maternal hematopoietic stem cell transplants for children, in the presence of microchimerism, may be associated with hyporesponsiveness to the inherited paternal HLA antigens (IPA); preventing severe GVHD.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adolescent , Female , Humans , Mothers , Time Factors , Tissue Donors , Treatment Outcome , Whole-Body IrradiationABSTRACT
We describe two separate episodes of hemophagocytic syndrome (HPS) at an interval of two years in a seemingly immunocompetent male. This case suggests the possible existence of an inherent predisposition to HPS, in which otherwise negligible self-limited viral infection may trigger HPS. Laboratory data for a 16-year-old boy admitted with persistent high grade fever and severe thrombocytopenia disclosed coagulation abnormality, liver damage, and hypercytokinemia. A bone marrow aspiration revealed a proliferation of histiocytes with fresh hemophagocytosis. We diagnosed that he was suffering from HPS. Responding to steroid pulse therapy, he recovered completely and was discharged. After two years of healthy life, he became febrile again and was readmitted. The fever was refractory to antibiotics and was associated with a sudden drop in platelet count. Laboratory data and the bone marrow picture were consistent with those of HPS. He was again successfully treated with steroid. After the second episode, he has been healthy for more than two years.
Subject(s)
Histiocytosis, Non-Langerhans-Cell , Adolescent , Disease Susceptibility , Fever/etiology , Histiocytosis, Non-Langerhans-Cell/diagnosis , Histiocytosis, Non-Langerhans-Cell/immunology , Humans , Immunocompetence , Male , Recurrence , Thrombocytopenia/etiologyABSTRACT
The 5q- syndrome is a myelodysplastic disorder characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5 as a solitary cytogenetic abnormality. The majority of patients with this syndrome are elderly women exhibiting red blood cell transfusion-dependent refractory anemia with a normal-to-increased number of platelets and modest granulocytopenia. The prognosis is relatively favorable with a low incidence of leukemic transformation. We report on a patient with 5q- syndrome associated with autoimmune hemolytic anemia (AHIA) and severe erythroid hypoplasia mimicking pure red cell aplasia (PRCA). A 65-year-old woman was admitted because of severe anemia. Elevated serum levels of LDH and indirect bilirubin, and a positive direct Coombs' test suggested AIHA associated with a huge ovarian dermoid cyst. However, lack of peripheral reticulocytes and bone marrow eryhroblasts, characteristic megakaryocytic morphology, and solitary 5q- anomaly favored a diagnosis of 5q- syndrome complicated by PRCA-like feature. Underlying immunological abnormalities ascribed to aberrant lymphoid clones intrinsic to MDS may be responsible for red cell aplasia and autoantibodies against red blood cells.