Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hairy cells are characterized by their typical morphology and expression of specific surface antigens. Although their B-cell origin is now confirmed, their exact position in B-cell development remains unclear. To better define the origin of hairy cells, we analysed the immunophenotype and the Ig VH nucleotide sequence of seven cases of hairy cell leukaemia (HCL). Six of them were typical HCL and the remaining case corresponded to a variant HCL. Analysis of sequenced VH genes revealed that the VH1 family was used in one case, VH2 in one, VH3 in two, VH4 in two and VH5 in one. No preferential usage of VH genes was observed in this small series. In five cases high rates of somatic mutations were observed, with a predominance of mutations and replacements in CDR regions for three. indicating that these cells originate from cells that have been exposed to the hypermutation mechanism. The distribution of mutations in our small series provides some evidence of a selective mutational process.
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PMID:VH gene expression in hairy cell leukaemia. 957 98

The t(16;21)(q24;q22) translocation is a rare but recurrent chromosomal abnormality associated with therapy-related myeloid malignancies and a variant of the t(8;21) translocation in which the AML1 gene on chromosome 21 is rearranged. Here we report the molecular definition of this chromosomal aberration in four patients. We cloned cDNAs from the leukemic cells of a patient carrying t(16;21) by the reverse transcription polymerase chain reaction using an AML1-specific primer. The structural analysis of the cDNAs showed that AML1 was fused to a novel gene named MTG16 (Myeloid Translocation Gene on chromosome 16) which shows high homology to MTG8 (ETO/CDR) and MTGR1. Northern blot analysis using MTG16 probes mainly detected 4.5 kb and 4.2 kb RNAs, along with several other minor RNAs in various human tissues. As in t(8;21), the t(16;21) breakpoints occurred between the exons 5 and 6 of AML1, and between the exons 1 and 2 or the exons 3 and 4 of MTG16. The two genes are fused in-frame, resulting in the characteristic chimeric transcripts of this translocation. Although the reciprocal chimeric product, MTG16-AML1, was also detected in one of the t(16;21) patients, its protein product was predicted to be truncated. Thus, the AML1-MTG16 gene fusion in t(16;21) leukemia results in the production of a protein that is very similar to the AML1-MTG8 chimeric protein.
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PMID:The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. 959 46

CAMPATH-1 antibodies have a long and successful history in the treatment of leukaemia, autoimmune disease and transplant rejection. The first antibody to undergo "humanisation", CAMPATH-1H, permits treatment with limited patient anti-globulin response. It recognises the CD52 antigen which is a small glycosylphosphatidylinositol(GPI)-anchored protein expressed on lymphocytes and mediates cell depletion. We present the 1.9 A structure of the CAMPATH-1H Fab complexed [corrected] with an analogue of the antigenic determinant of CD52. Analysis of the CAMPATH-1H binding site reveals that in contrast to most antibodies CDR L3 plays a dominant role in antigen binding. Furthermore CDR H3, which is essential for effective antigen recognition in most antibodies, participates in only two main-chain interactions in CAMPATH-1H. The CAMPATH-1H binding site is highly basic; ionic interaction with the enthanolamine phosphate of the CD52 GPI anchor has long been hypothesised to be important in antigen binding. The structure reveals a number of important specific ionic interactions, including Lys53H but not Lys52bH as had previously been suggested. Prolonged treatment with CAMPATH-1H can lead to patient anti-idiotype responses which may be exacerbated by the unusually high number of basic residues in the antibody. This suggests that a strategy where redundant basic residues are replaced with neutral counterparts may be effective in further reducing the immunogenicity of this versatile and widely used antibody.
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PMID:1.9 A structure of the therapeutic antibody CAMPATH-1H fab in complex with a synthetic peptide antigen. 1036 6

Two novel B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) cell lines, designated NALM-33 and NALM-34, were established from a 72 year-old male patient with ALL at relapse. Subcultures of each initial flask were first made after eight weeks of continuous incubation; thus, the two cell lines are simultaneous sister cell lines. The cells proliferate consistently singly and free-floating in suspension. They are negative for Epstein-Barr virus (EBV) infection by polymerase chain reaction (PCR) and are negative for mycoplasma infection. They have the morphological appearance of lymphoblasts with a scanty rim of cytoplasm, fine nuclear chromatin and distinct nucleoli. The primary leukemic blasts showed a common ALL phenotype with CD19+, CD10+, CD13-, HLA-DR+ and Igs-; the cell lines NALM-33/-34 display an identical immunophenotype. They fulfill "European Group for the Immunological Characterization of Leukemias (EGIL)" criteria as BCP leukemia B-II type. While the immunoglobulin heavy chain genes were found uniquely to be in their germline configuration, rearrangement of both kappa and lambda light chain genes was noted by Southern blot analysis. CDR-II detection by reverse transcriptase-PCR was also not detected. NALM-33/-34 did not respond significantly to the proliferative stimuli of various hematopoietic cytokines. In the cytogenetic analysis, they revealed the t(8;14)(q24.1;q32) with additional numerical and structural chromosomal abnormalities. The extensive immunological, cytogenetic and functional characterization of NALM-33/-34 suggests that these two novel cell lines may represent unique and relevant in vitro model systems for BCP-type leukemia cells.
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PMID:Novel B-cell precursor leukemia sister cell lines, NALM-33 and NALM-34, established from a patient with acute lymphoblastic leukemia. 1060 89

CD33 is expressed by acute myeloid leukemia (AML) cells in >80% of patients but not by normal hematopoietic stem cells, suggesting that elimination of CD33(+) cells may be therapeutically beneficial. A conjugate of a calicheamicin hydrazide derivative attached via hydrazone formation to the oxidized carbohydrates of the anti-CD33 murine antibody P67.6 had been chosen for use in AML prior to humanization of this antibody. However, the CDR-grafted humanized P67.6 could not be used to make the carbohydrate conjugate because of the unexpected sensitivity of this antibody to periodate oxidation. Exploration of a series of bifunctional linkers resulted in a new class of calicheamicin conjugates, termed the hybrid conjugates, that allows for the attachment of the calicheamicin to lysines but incorporates the site of hydrolytic release, a hydrazone, previously shown to be required for activity. The optimized conjugate chosen for clinical trials, gemtuzumab ozogamicin ("gem-ozo", Mylotarg, formerly designated CMA-676), was significantly more potent and selective than the carbohydrate conjugate it replaced. It was selectively cytotoxic to HL-60 leukemia cells in tissue culture with an IC(50) in the low to sub-pg cal/mL range (cal = calicheamicin equivalents). Doses of gem-ozo as low as 50 microg cal/kg given three times to mice bearing HL-60 xenografts routinely resulted in long-term, tumor-free survivors, while a nonbinding control conjugate was relatively inactive. Gem-ozo at a concentration of 2 to 10 ng cal/mL selectively inhibited leukemia colony formation by marrow cells from a significant proportion of AML patients. Gem-ozo has also shown significant activity against AML in Phase II trials and is the first antibody-targeted chemotherapeutic agent approved by the FDA.
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PMID:Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. 1179 78

Two vaccines against an intracellularly expressed B cell idiotype were assessed for their ability to induce protective immunity in mice against challenge with a pre-B cell leukemia. One vaccine was based on a plasmid expression vector and the other was a recombinant vaccinia virus; both vaccines expressed a polypeptide derived from the complementarity-determining regions (CDR(2)-CDR(3)) of the leukemic clone-specific immunoglobulin heavy chain (IgH), as a fusion product with mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF). Mice inoculated with either vaccine showed significantly higher survival rates than controls after challenge with leukemia cells. However, protection from tumor challenge was optimal when the DNA vaccine was used for priming, followed by a booster immunization with the vaccinia virus recombinant. This vaccination protocol induced resistance not only to the first tumor challenge given shortly afterwards, but also to a second challenge given months later. Both CD4(+) and CD8(+) T cells contributed to protection in vaccinated mice. These data suggest that such a vaccine regimen might reduce the incidence of recurrence in patients with minimal residual disease after conventional therapy.
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PMID:Prime-boost vaccines encoding an intracellular idiotype/GM-CSF fusion protein induce protective cell-mediated immunity in murine pre-B cell leukemia. 1194 75

A 32 year old female smoker (20 pack years) presented with an asymptomatic lymphocytosis of 13,000/nl and splenomegaly. The patient's blood smear showed an absolute lymphocytosis with 65% atypical lymphocytes. A total of 1% of the lymphocytes were bilobulated. Bone marrow histology and immunphenotyping of blood and bone marrow excluded leukemia and non-Hodgkin's lymphoma. IgH-CDR-3 PCR analysis revealed a polyclonal pattern. In summary, a persistent polyclonal B-cell-lymphocytosis (PPBL) was diagnosed. The exact etiology of PPBL is still unclear, however, it is associated with a polyclonal raise in the lymphocyte count of CD27+IgD+-memory-B-lymphocytes due to a defect in apoptosis signaling and leukocyte homing to secondary lymphoid tissues. An association with cigarette smoking is obvious since all patients are smokers. From all published cases, only two developed a malignancy with an uncertain association with PPBL. We have been monitoring our patient for 6.5 years without any evidence of the development of a lymphoma.
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PMID:[Asymptomatic 32 year old female smoker with persistent polyclonal lymphocytosis]. 1728 65


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