losartan-potassium and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

Pluripotent stem cells of hematopoiesis and lymphopoiesis are among the CD34+ cells in blood or bone marrow. After granulocyte-colony stimulating factor (G-CSF) treatment, 1% to 2% of the mononuclear cells in blood are CD34+ cells, which can be procured by leukapheresis. We investigated the potential of CD34+ blood cells for reconstituting hematopoiesis and lymphopoiesis after allogeneic transplantation. HLA-identical sibling donors of 10 patients with hematologic malignancies were treated with G-CSF (filgrastim), 5 microgram/kg subcutaneously twice daily for 5 to 7 days. CD34+ cells were selected from the apheresis concentrates by immunoadsorption, concomitantly the number of T cells was reduced 100- to 1,000-fold. After transplantation, five patients received cyclosporine A for graft-versus-host disease (GvHD) prophylaxis (group I); five patients additionally received methotrexate (group II). G-CSF and erythropoietin were given to all patients. Mean numbers of 7.45 x 10(6) CD34+ and 1.2 x 10(6) CD3+ cells per kilogram were transplanted. In group I, the median times of neutrophil recovery to 100, 500, and 1,000 per mm3 were 10, 10, and 11 days, respectively. Group II patients reached these neutrophil levels after 10, 14, and 15 days, respectively. Platelet transfusions were administered for a median of 18 days in group I and 30 days in group II, and red blood cells for 9 and 12 days, respectively. Between day 30 and 60, lymphocytes reached levels of 353 +/- 269 cells per mm3. The median grades of acute GvHD were III in group I and I in group II. Two patients in group I died from acute GvHD. Two leukemic relapses occurred in group II. Complete and stable donor hematopoiesis was shown in all patients with a median follow up of 370 (45 to 481) days. Allogeneic blood CD34+ cells can successfully reconstitute hematopoiesis and lymphopoiesis. Reduction of T cells by CD34+ blood cell enrichment and cyclosporine A alone might not be sufficient for prophylaxis of severe acute GvHD.

Topics: Acute Disease; Adult; Antigens, CD34; Bone Marrow; Cell Division; Cyclosporine; Erythropoietin; Female; Filgrastim; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunosuppressive Agents; Leukapheresis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Platelet Transfusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; T-Lymphocytes; Transplantation, Homologous

Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays key roles in hematopoietic and immune responses. The acquired JAK2 R683G(S) somatic mutations are detected in 15% of patients with B-cell acute lymphoblastic leukemia (B-ALL) and are presumed to be a biomarker for B-ALL. However, how JAK2 R683G(S) mutations lead to B-ALL is still unclear. Our results indicated that the E627 and R683 interaction played a vital role in JAK2 autoinhibition. Mutations (R683S, R683G and E627A) disrupting this interaction led to JAK2 constitutive activation, while mutations (R683K, E627D) restoring this interaction decreased its activity. Furthermore, spectroscopy experiments implied that disruption of the E627 and R683 interaction abolished JH1/JH2 domain interactions and forced the JH1 domain into the open, active conformation. Mutations abolishing this interaction promoted the proliferation of Ba/F3 cells. The results herein may provide clues to understanding the mechanism of JAK2 R683G(S) mutation-associated B-ALL.

Topics: Cell Line, Tumor; Cell Proliferation; Codon; Enzyme Activation; Erythropoietin; Humans; Janus Kinase 2; Models, Molecular; Mutation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Protein Conformation; Protein Interaction Domains and Motifs

The anomalous EVI1 rearrangements/t(3;3)(q21;q26) is more frequently found in myelocytic malignancies. 5q- syndrome is a newly defined subtype of myelodysplastic syndrome (MDS) first proposed by the World Health Organization in 2001. Cases of acute lymphocytic leukemia (ALL) with 5q- anomaly or t(3;3)/EVI1 rearrangement have rarely been reported. We report a rare 5q- syndrome case which ultimately transformed to acute lymphocytic leukemia accompanied by a secondary cytogenetic anomaly of t(3;3)(q21;q26) and EVI1 rearrangement around 3 years after the diagnosis of 5q- syndrome. This rare case suggests that the 5q- clone of MDS may originate from a multipotent cell with a capacity to differentiate toward both myeloid and lymphoid lineages. It also indicates that although the t(3;3)/EVI1 rearrangement is mostly related to myelocytic neoplasms, the t(3;3)/EVI1-rearrangement may also play an important role in the development of ALL. The results of the necessary tests must be analyzed sufficiently prior to making a final diagnosis.

Topics: Adult; Anemia, Macrocytic; Blood Transfusion; Bone Marrow; Cell Differentiation; Cell Lineage; Chromosome Deletion; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 5; Disease Progression; DNA-Binding Proteins; Erythropoietin; Fatal Outcome; Fatigue; Humans; Immunophenotyping; Karyotype; Male; MDS1 and EVI1 Complex Locus Protein; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogenes; Testosterone; Thalidomide; Transcription Factors