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V Najfeld

Publications and source records attributed to V Najfeld.

At least 37 records · Page 2Linked to original sources
PubMed1997

Evidence for the embryonic origin of partial chromosome 7 deletion in monozygotic twins with juvenile chronic myelogenous leukemia.

During donor evaluation for allogeneic bone marrow transplantation (BMT) of a 28-month-old child with juvenile chronic myelogeneous leukemia (JCML) with 46,XY,-7,+mar karyotype, the potential donor twin brother was found to be thrombocytopenic. Subsequent genotype analysis determined monozygosity with 98% probability. Bone marrow analysis of the twin brother revealed the same 46,XY,-7,+mar karyotype and a diagnosis of JCML was made. Metaphase FISH studies documented that mar chromosome in both twins contains the pericentromeric region of chromosome 7 and thus both twins had a partial monosomy of chromosome 7. A possible embryonic origin of del(7) is proposed.

Antineoplastic Agents↗
PubMed1997

Disparate lympho-erythroid donor to recipient chimaerism in a beta(0)-thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment.

A 4-year-old girl with transfusion-dependent beta(0)-thalassaemia received an HLA-identical bone marrow transplant (BMT) from her beta(0)-thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post-BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU-E) was analysed. On days 1000 and 1130 post-BMT, 79% and 77% of colonies, respectively, synthesized beta-globin and therefore were of donor origin.

Bone Marrow Transplantation↗
PubMed1995

Localization of PURA, the gene encoding the sequence-specific single-stranded-DNA-binding protein Pur alpha, to chromosome band 5q31.

Pur alpha (PurA) is a sequence-specific single-stranded-DNA-binding protein implicated in control of both DNA replication and transcription. We have localized the Pur alpha gene (PURA) to human chromosome band 5q31 by fluorescence in situ hybridization with a 16-kb genomic probe together with hybridization of a cDNA probe to blots of DNA from human-hamster cell lines containing individual human chromosomes. Sequences with homology to the PURA locus are also present at 6q14. The 5q31 locus is frequently deleted in myelogenous leukemia and other cancers.

Animals↗
PubMed1995

Jumping translocations in leukemia.

Jumping translocations are an unusual phenomenon and have been rarely reported in leukemia. We report three patients whose leukemic cells had multiple related clones resulting from unbalanced jumping translocations of 1q and 7q to chromosomes 1, 8, 15, 21 and 22. The chromosome findings, together with limited published reports, suggest that jumping translocations are new non-random rearrangements and may represent poor prognostic biological markers. Although their origin is unknown, circumstantial evidence suggests that telomeric ends of receptor chromosomes may play a role in stabilizing jumping translocations in dividing malignant cells.

Anemia, Refractory, with Excess of Blasts↗
PubMed1994

Myelodysplastic syndrome transforming to acute promyelocytic-like leukemia with trisomy and rearrangement of chromosome 11.

Variants of the t(15;17)(q22;q12-q21) chromosomal rearrangement associated with acute promyelocytic leukemia (APL) have been previously described and they frequently involve either chromosome 15 and/or 17. Previously we reported a rare variant t(11;17). We now describe two patients with myelodysplastic syndrome (MDS) that transformed to APL-like leukemia. Both had trisomy 11 at the diagnosis of APL-like leukemia. Following treatment for APL, patient 1 reverted to MDS and showed a normal karyotype. When leukemia recurred, his bone marrow karyotype was 47,XY,t(4;11), +11,der(22)t(1;22). Both patients were treated with all-trans retinoic acid (ATRA) for APL for 5 weeks, but failed to respond. The karyotype of patient 1 after ATRA treatment was 46,XY,t(4;11); the trisomy 11 had been lost and the bone marrow was replaced with immature myeloblasts without promyelocytes. In patient 2, the karyotype remained the same as at diagnosis, i.e., 47,X,-Y,dir ins(4;7),del(5), +6,del(7), +8, + 11,-18. Molecular analysis by reverse transcriptase PCR analysis showed the presence of wild type retinoic acid receptor alpha (RARA) and the absence of the PML-RARA chimeric gene associated with t(15;17). Additional analysis of PLZF, a new zinc finger gene associated with t(11;17), also showed the absence of this hybrid gene. These data support the concept that APL is a heterogeneous disorder and that variants with chromosome 11 rearrangement exist that do not respond to ATRA.

Adult↗
PubMed1993

Genomic structure and chromosomal mapping of the human CD22 gene.

The human CD22 gene is expressed specifically in B lymphocytes and likely has an important function in cell-cell interactions. A nearly full length human CD22 cDNA clone was used to isolate genomic clones that span the CD22 gene. The CD22 gene is spread over 22 kb of DNA and is composed of 15 exons. The first exon contains the major transcriptional start sites. The translation initiation codon is located in exon 3, which also encodes a portion of the signal peptide. Exons 4 to 10 encode the seven Ig domains of CD22, exon 11 encodes the transmembrane domain, exons 12 to 15 encode the intracytoplasmic domain of CD22, and exon 15 also contains the 3' untranslated region. A minor form of CD22 mRNA likely results from splicing of exon 5 to exon 8, skipping exons 6 and 7. A 4.6-kb XbaI fragment of the CD22 gene was used to map the chromosomal location of CD22 by fluorescence in situ hybridization. The hybridization locus was identified by combining fluorescent images of the probe with the chromosomal banding pattern generated by an Alu probe. The results demonstrate that CD22 is located within the band region q13.1 of chromosome 19. Two closely clustered major transcription start sites and several minor start sites were mapped by primer extension. Similarly to many other lymphoid-specific genes, the CD22 promoter lacks an obvious TATA box. Approximately 4 kb of DNA 5' of the transcription start sites were sequenced and found to contain multiple Alu elements. Potential binding sites for the transcriptional factors NF-kappa B, AP-1, and Oct-2 are located within 300 bp 5' of the major transcription start sites. A 400-bp fragment (bp -339 through +71) of the CD22 promoter region was subcloned into a pGEM-chloramphenicol acetyltransferase vector and after transfection into B and T cells was found to be active in both B and T cells. Further studies of the CD22 gene should lead to a greater understanding of the expression of CD22 during B cell development and differentiation.

Antigens, CD↗
PubMed1993

Clonal chromosomal abnormalities in Fanconi's anaemia: what do they really mean?

Patients with Fanconi's anaemia (FA) have aplastic anaemia, leukaemia, myelodysplasia and tumours. Since leukaemia has a very poor prognosis, it is desirable to identify high-risk patients. To determine the significance of clonal marrow chromosomal abnormalities we began a prospective study in 17 patients: five were normal, eight aplastic, and four myelodysplastic. Three of 11 with adequate cytogenetics had transient abnormal clones. None had leukaemia at 3-24 months. Changing cytogenetic patterns may not be related to leukaemic evolution in patients with a DNA repair defect.

Chromosome Aberrations↗
PubMed1993

High expression of two diverged homeobox genes, HB24 and HB9, in acute leukemias: molecular markers of hematopoietic cell immaturity.

Homeobox genes encode for sequence-specific DNA-binding proteins which have been implicated in the control of gene expression during development and in certain adult tissues. Two recently characterized human homeobox-containing genes, HB9 and HB24, are known to be expressed in hematopoietic progenitors and to be involved in the regulation of growth and differentiation of progenitor cells to mature hematopoietic cell types. In this study, elevated levels of HB24 and HB9 mRNA expression were detected in bone marrow and peripheral blood mononuclear cells (PBMC) isolated from patients with acute myelogenous or acute lymphocytic leukemia. While the levels of both mRNAs were elevated in all the patients with acute leukemias, the levels of HB9 mRNA were more variable than those of HB24. Immunohistochemical analysis utilizing an HB24 polyclonal antiserum demonstrated elevated levels of HB24 protein in cytopreparations of acute leukemic cells. Nuclear run-on experiments showed that the increases of HB9 and HB24 mRNA transcripts in patients' cells were, at least in part, secondary to increased transcription. The expression of HB9 and HB24 correlated with the clinical status of the patient. No significant level of expression of either HB9 or HB24 was detected in PBMC isolated from patients in remission. In contrast to the findings with cells isolated from patients with acute leukemias, no significant increase in either HB9 or HB24 transcript levels were found in cells from patients with chronic lymphocytic or chronic myelogenous leukemia when compared to normal controls. These findings demonstrate that high levels of HB9 and HB24 expression are common features of acute leukemia and suggest the possibility that the dysregulated expression of these two genes may contribute to leukemogenesis. However, since these two genes are markers of immature hematopoietic cells they may not have an etiologic role in leukemogenesis.

Acute Disease↗
PubMed1993

Further evidence for the existence of a clonal Ph-negative stage in some cases of Ph-positive chronic myelocytic leukemia.

The Ph chromosome abnormality is involved in the pathogenesis of almost all patients with chronic myelocytic leukemia (CML). Previous studies on the B-lymphoid cell lineage in two patients with Ph-positive CML suggest that there may also be a clonal Ph-negative stage in CML and that the Ph-positive stage arises by subclonal expansion. To determine whether this is a frequent or a rare occurrence, 14 additional glucose-6-phosphate dehydrogenase (G6PD)-heterozygous patients with CML were studied. In five of these patients there was a statistically significant excess of Ph-negative B-lymphoid cell lines expressing the same G6PD type expressed in the corresponding CML clone. In no case was an excess of B-lymphoid lines expressing the opposite G6PD type recovered. These data provide further evidence that in some patients the Ph chromosome arises in a pluripotent stem cell from a pre-existing Ph-negative clone that enjoys a growth advantage.

Adult↗
PubMed1992

del(5q) in acute lymphoblastic leukemia with biphenotypic and early progenitor phenotype.

We report three patients with acute lymphoblastic leukemia with biphenotypic and early progenitor phenotype who had del(5q). In the first patient, the del(5q) was the sole abnormality; in the second patient, the del(5q) was interpreted as subclonal evolutionary event; while in the third patient, the rearrangement was transiently present 7 months following the diagnosis of Ph-positive ALL, while the patient was in clinical remission. Review of the literature indicates that del(5q) is rare in ALL. In contrast to its presence in AML, del(5q) in ALL is not an adverse prognostic indicator, and it appears to be more frequent in children.

Adolescent↗
PubMed1992

Differences in the frequency of normal and clonal precursors of colony-forming cells in chronic myelogenous leukemia and acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is a clonal disease that is heterogeneous with respect to the pattern of differentiative expression of the leukemic progenitors. In some patients, the involved stem cells manifest pluripotent differentiative expression, whereas in others, the involved progenitors manifest differentiative expression mainly restricted to the granulocytic pathway. This is in contrast to chronic myelogenous leukemia (CML) which is a clonal disease known to arise in a pluripotent stem cell. Therefore, we tested whether these leukemias could be distinguished with respect to their involvement of immature precursors by studying colony-forming cells (CFC) and their precursors from four glucose-6-phosphate dehydrogenase (G6PD) heterozygous patients with AML and five patients with CML. CFC were separated from their precursors by FACS for expression of CD33 and CD34 followed by growth in a long-term culture (LTC) system. The vast majority of CFC express both the CD33 and CD34 antigens, but their less mature precursors, detected by their ability to give rise to CFC in LTC, express only CD34. In three of the four patients with AML, the CD33-CD34+ cells produced CFC in LTC that appeared to be predominantly or completely normal (ie, nonclonal) in origin. In the fourth patient, a significant enrichment of nonclonal progenitors was obtained in the CD33-CD34+ population, but these cells may also have included significant numbers of clonal cells. In contrast, in four of five patients with CML, cultures of both the CD33-CD34+ and CD33+CD34+ populations produced CFC in LTC that were almost entirely clonal in origin, whereas in the fifth patient a substantial number originated from nonclonal stem cells. These data indicate that granulocyte/monocyte progenitors are predominantly clonally derived in CML and AML. In CML, their precursors are also predominantly clonal, but in some cases of AML they are not. These findings may have implications for understanding the success or failure of current therapies of AML and CML.

Antigens, CD↗
PubMed1992

Two diverged human homeobox genes involved in the differentiation of human hematopoietic progenitors map to chromosome 1, bands q41-42.1.

Proteins encoded by homeobox containing genes are sequence-specific DNA binding proteins implicated in the control of gene expression in both developing and adult tissues. Two recently characterized human homeobox genes, HB9 and HB24, are highly expressed in CD34-positive marrow cells but not in CD34-depleted marrow cells. Their expression is readily down-regulated during the differentiation of hematopoietic progenitors to specific cell lineages. In this study, genomic DNA fragments isolated with HB9 (3 kb) and HB24 (6 kb) cDNAs were used to map their chromosomal location by fluorescence in situ hybridization. Both HB9 and HB24 DNA probes gave specific hybridization signals on chromosome 1. The hybridization loci were identified by combining fluorescence images of the probe signals with fluorescence banding patterns generated by cohybridization in situ with an Alu probe (R-like banding) and by DAPI staining (G-like). The results demonstrate that the loci of the HB24 and HB9 genes are within bands 1q41-q42.1. A cohybridization experiment utilizing both probes with two-color fluorescence imaging could not resolve separate loci for the two genes.

Cell Differentiation↗
PubMed1992

Chromosome 21 rearrangement in acute biphenotypic leukemia.

A patient with myelodysplastic syndrome (MDS) and a 47,XY,+21 karyotype at diagnosis, was documented to have a clonal chromosome 21 rearrangement, i(21q), four months before transformation to acute biphenotypic leukemia. For 4 months after transformation, isochromosome 21 persisted while the patient was receiving treatment with zidovudine. Vitamin D3 was added to zidovudine for an additional month, during which time the trisomy 21 clone reappeared as the predominant cell population. The unique aspects of this patient are the atypical evolution of chromosome 21, the transformation to biphenotypic leukemia, and the occurrence of i(21q) associated with biphenotypic leukemia evolving from an MDS.

Anemia, Refractory, with Excess of Blasts↗
PubMed1992

Allogenic bone marrow transplantation in severe Gaucher disease.

Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.

Bone Marrow Transplantation↗