Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a clinical case of chronic myelogenous leukaemia (CML) with regional B-lymphoblastic transformation. Peripheral leukocytosis of 160 x 10(9)/L, splenomegaly and fatigue suggested CML. In peripheral blood and bone marrow smears, white blood cells in all maturation stages and only few blasts were seen and therefore the diagnosis of chronic phase CML was proposed. Cytogenetics performed on peripheral blood cells revealed the characteristic t(9;22)(q34;q11) translocation as solitary abnormality. Analyzing the bone marrow biopsy a focal nodular B-lymphoid blast component was additionally seen. BCR-ABL FISH analysis demonstrated 31% atypical split signals in the B-lymphoid blasts and in the maturing myeloid cells, furthermore, BCR-ABL fusion transcripts were seen in the RT-PCR assay. Imatinib-based therapy led to temporary regression of peripheral leukocytosis. Bone marrow examination 3 weeks after therapy induction demonstrated considerably reduced cellularity and the proportion of B-lymphoid blasts had decreased to 20% of the nuclear cells. BCR-ABL FISH analysis still presented 21% atypical split signals but levels of BCR-ABL transcripts had significantly fallen indicating a rather favourable prognosis. However, 3 months after diagnosis the patient relapsed and developed an immunodeficiency with soor esophagitis and aspergillus pneumonia. A therapy with dasatinib was not successful and the patient died in consequence of immunodeficiency. This report demonstrates the high diagnostic value of bone marrow biopsy in the evaluation of CML. Besides morphology investigation of diverse methods including RT-PCR and FISH performed on diagnostic bone marrow biopsies are obligatory for ideal monitoring of drug response.
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PMID:High diagnostic value of morphologic examination and molecular analysis of bone marrow biopsies in a case of BCR-ABL+ CML with clusters of blasts. 1922 89

Antigen receptor gene assembly is accomplished in developing lymphocytes by the V(D)J recombination reaction, which can be separated into two steps: DNA cleavage by the recombination-activating gene (RAG) nuclease and joining of DNA double strand breaks (DSBs) by components of the nonhomologous end joining (NHEJ) pathway. Deficiencies for NHEJ factors can result in immunodeficiency and a propensity to accumulate genomic instability, thus highlighting the importance of identifying all players in this process and deciphering their functions. Bcl2 transgenic v-Abl kinase-transformed pro-B cells provide a pseudo-physiological cellular system to study V(D)J recombination. Treatment of v-Abl/Bcl2 pro-B cells with the Abl kinase inhibitor Imatinib leads to G1 cell cycle arrest, the rapid induction of Rag1/2 gene expression and V(D)J recombination. In this system, the Bcl2 transgene alleviates Imatinib-induced apoptosis enabling the analysis of induced V(D)J recombination. Although powerful, the use of mouse models carrying the Bcl2 transgene for the generation of v-Abl pro-B cell lines is time and money consuming. Here, we describe a method for generating v-Abl/Bcl2 pro-B cell lines from wild type mice and for performing gene knock-out using episomal CRISPR/Cas9 targeting vectors. Using this approach, we generated distinct NHEJ-deficient pro-B cell lines and quantified V(D)J recombination levels in these cells. Furthermore, this methodology can be adapted to generate pro-B cell lines deficient for any gene suspected to play a role in V(D)J recombination, and more generally DSB repair.
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PMID:Generation and CRISPR/Cas9 editing of transformed progenitor B cells as a pseudo-physiological system to study DNA repair gene function in V(D)J recombination. 2888 11