Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
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PMID:Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. 1712 67

The treatment of myeloid leukaemia has progressed in recent years with the advent of donor leukocyte infusions (DLI), haemopoietic stem cell transplants (HSCTs) and targeted therapies. However, relapse has a high associated morbidity rate and a method for removing diseased cells in first remission, when a minimal residual disease state is achieved and tumour load is low, has the potential to extend remission times and prevent relapse especially when used in combination with conventional treatments. Acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are heterogeneous diseases which lack one common molecular target while chronic myeloid leukaemia (CML) patients have experienced prolonged remissions through the use of targeted therapies which remove BCR-ABL(+) cells effectively in early chronic phase. However, escape mutants have arisen and this therapy has little effectivity in the late chronic phase. Here we review the immune therapies which are close to or in clinical trials for the myeloid leukaemias and describe their potential advantages and disadvantages.
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PMID:Immunotherapy of myeloid leukaemia. 1718 Jun 71

NUP98-HOXD13 (NHD13) fusions have been identified in patients with myelodysplastic syndrome, acute myelogenous leukemia and chronic myeloid leukemia blast crisis. We generated 'knock-in' mouse embryonic stem (ES) cells that express a NHD13 fusion gene from the endogenous murine NUP98 promoter, and used an in vitro differentiation system to differentiate the ES cells to hematopoietic colonies. Replating assays demonstrated that the partially differentiated NHD13 ES cells were immortal, and two of these cultures were transferred to liquid culture. These cell lines are partially differentiated immature hematopoietic cells, as determined by morphology, immunophenotype and gene expression profile. Despite these characteristics, they were unable to differentiate when exposed to high concentrations of erythropoietin (Epo), granulocyte colony-stimulating factor or macrophage colony-stimulating factor. The cell lines are incompletely transformed, as evidenced by their dependence on interleukin 3 (IL-3), and their failure to initiate tumors when injected into immunodeficient mice. We attempted genetic complementation of the NHD13 gene using IL-3 independence and tumorigenicity in immunodeficient mice as markers of transformation, and found that BCR-ABL successfully transformed the cell lines. These findings support the hypothesis that expression of a NHD13 fusion gene impairs hematopoietic differentiation, and that these cell lines present a model system to study the nature of this impaired differentiation.
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PMID:Mouse embryonic stem cells that express a NUP98-HOXD13 fusion protein are impaired in their ability to differentiate and can be complemented by BCR-ABL. 1737 91

Reciprocal translocations involving the long arm of chromosome 7 are relatively rare cytogenetic aberrations in myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). A 44-year-old woman was initially given a diagnosis of de novo AML M6A with a normal karyotype. After achieving complete remission, she received allogeneic bone marrow transplantation from an unrelated male donor. Seven months later, pancytopenia appeared with 14.8% myeloblasts and dysplastic changes of neutrophils and megakaryocytes in the bone marrow. Chromosome analysis revealed complex karyotypes, with add(7)(q22) and add(9)(q34) detected in all abnormal metaphase spreads; spectral karyotyping revealed these chromosomal aberrations to be derived from a reciprocal translocation t(7;9)(q22;q34). Fluorescence in situ hybridization analyses showed that D7S486 at 7q31 was translocated to the der(9)t(7;9), and that the ABL gene at 9q34 remained on the der(9)t(7;9). Because the same translocation reappeared and sustained for more than 8 months after second stem cell transplantation, we revised the diagnosis as therapy-related MDS after allogeneic transplantation. The t(7;9)(q22;q34) was supposed to have a crucial role in the pathogenesis of MDS. Considering two other such reported cases of AML, the t(7;9)(q22;q34) may be a novel recurrent translocation in myeloid malignancies.
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PMID:Translocation (7;9)(q22;q34) in therapy-related myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloblastic leukemia. 1757 66

The Philadelphia (Ph) chromosome, or t(9;22), is the hallmark of chronic myelogenous leukemia (CML). It results in juxtaposition of the 5' part of the BCR gene on chromosome 22 to the 3' part of the ABL1 gene (previously ABL) on chromosome 9. CML is clinically characterized by three distinct phases: chronic, accelerated, and blast phase. Blast crisis is characterized by the rapid expansion of a population of differentiation arrested blast cells (myeloid or lymphoid cells population), with secondary chromosomal abnormalities present. We report a case of myeloid blast crisis of CML resistant to imatinib mesylate and chemotherapy. By use of cytogenetic, fluorescence in situ hybridization, and comparative genomic hybridization methods, we identified a cluster of BCR-ABL amplification on inverted duplication of the Ph chromosome with t(3;21)(q26;q22) and increased genomic levels of the RUNX1 gene (previously AML1). The t(3;21)(q26;q22) is a recurrent chromosomal abnormality in some cases of CML blast phase and in treatment-related myelodysplastic syndrome and acute myeloid leukemia. Amplification or copy number increase of RUNX1 has been reported in childhood acute lymphoblastic leukemia. Our study indicated that the progenitor of CML was BCR-ABL dependent through the amplification of Ph chromosome as a mechanism of resistance to imatinib therapy. The coexistence of BCR-ABL and t(3;21)(q26;q22) with RUNX1 rearrangement might play a pivotal role in the CML blast transformation.
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PMID:Amplification of BCR-ABL and t(3;21) in a patient with blast crisis of chronic myelogenous leukemia. 1806 36

Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
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PMID:RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance. 1820 28

Disease progression in myeloid malignancies results from the accumulation of "mutations" in genes that control cellular growth and differentiation. Many types of genetic alterations have been identified in myeloid diseases. However, the mechanism(s) by which these cells acquire genetic alterations or "Genomic instability", is less well understood. Increasing evidence suggests that the genetic changes in myeloid malignancies lead to increased production of endogenous sources of DNA damage, such as, reactive oxygen species (ROS). The fusion gene BCR-ABL in chronic myeloid leukemia (CML), FLT3/ITD in acute myeloid leukemia (AML), and RAS mutations in myelodysplastic syndromes (MDS)/myeloproliferative diseases (MPD) result in ROS production. Increased ROS can drive a cycle of genomic instability leading to DNA double strand breaks (DSBs) and altered repair that can lead to acquisition of genomic changes. Evidence is coming to light that defects in a main repair pathway for DSBs, non-homologous end-joining (NHEJ), lead to up-regulation of alternative or "back-up" repair that can create chromosomal deletions and translocations. This article will review evidence for activation of RAS/PI3K/STAT pathways, that lead to increased ROS, DNA damage and defective repair in myeloid diseases, a mechanism for acquisition of additional mutations that can drive disease progression.
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PMID:Genomic instability in myeloid malignancies: increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair. 1846 25

Abnormal nuclear megakaryocytic staining for phospho-STAT5 (pSTAT5) correlates with JAK2 V617F mutational status in non-chronic myelogenous leukemia chronic myeloproliferative disorders. However, a proportion of wild-type JAK2 non-chronic myelogenous leukemia chronic myeloproliferative disorders cases also demonstrate this abnormal pSTAT5 expression pattern. We report a patient with a JAK2 V617F-negative myeloproliferative/myelodysplastic syndrome who had abnormal megakaryocytic pSTAT5 expression and a MPL W515L mutation. The patient was a 71-year-old man with anemia and thrombocythemia on laboratory examination. His peripheral blood smear demonstrated occasional dysplastic neutrophils. Bone marrow biopsy revealed hypercellular marrow with features consistent with myeloproliferative/myelodysplastic syndrome. Immunohistochemistry for pSTAT5 showed abnormal nuclear megakaryocyte positivity. Cytogenetic analysis revealed a normal karyotype, fluorescence in situ hybridization for BCR-ABL was negative, and JAK2 genotyping demonstrated wild-type JAK2. However, MPL genotyping showed a MPL W515L mutation. Abnormal nuclear megakaryocytic staining for pSTAT5 expression, previously associated with the JAK2 V617F mutation, is also associated with MPL W515L, likely reflecting activation of the JAK-STAT signaling pathway.
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PMID:Phospho-STAT5 expression pattern with the MPL W515L mutation is similar to that seen in chronic myeloproliferative disorders with JAK2 V617F. 1847 30

Advances in the therapy of malignancy have been accompanied by an increased frequency of cases of secondary acute myelogenous leukemia and related clonal cytopenias and oligoblastic (subacute) myelogenous leukemia (myelodysplastic syndromes). The acute myelogenous leukemia incidence can be increased by high-dose acute ionizing radiation exposure, alkylating agents, topoisomerase II inhibitors, possibly other DNA-damaging therapeutic agents, heavy, prolonged cigarette smoking, and high dose-time exposure to benzene, the latter less frequently seen in industrialized countries with worksite regulations. Acute myelogenous leukemia and myelodysplastic syndromes may result from innumerable primary types of chromosome damage. In the case of chronic myelogenous leukemia, a specific break in chromosome bands 9q34 and 22q11 must occur to result in the causal fusion oncogene (BCR-ABL). A review of 11 studies of the chromosomal abnormalities found in presumptive cases of cytotoxic therapy-induced leukemia and of 40 studies of the subtypes of leukemia that occur following cytotoxic therapy for other cancers has not provided evidence of an increased risk for chemically induced BCR-ABL-positive chronic myelogenous leukemia. Studies of the effects of alkylating agents, topoisomerase inhibitors, and benzene on chromosomes of hematopoietic cells in vitro, coupled with the aforementioned epidemiological studies of secondary leukemia after cytotoxic therapy or of persons exposed to high dose-time concentrations of benzene in the workplace, do not indicate a relationship among chemical exposure, injury to chromosome bands 9q34 and 22q11, and an increased risk for BCR-ABL-positive chronic myelogenous leukemia.
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PMID:Is there an entity of chemically induced BCR-ABL-positive chronic myelogenous leukemia? 1858 19

Allogeneic SCT is important in myelodysplastic syndrome, the BCR-ABL-negative chronic myeloproliferative diseases (CMPDs) and in poor-risk AML. Techniques to monitor the minimal residual disease, for example, by PCR or immunophenotyping gain increasing importance in the post transplantation period as basis for improved and earlier therapeutic interventions in impending relapse. Recent markers such as the NPM1 mutations in AML or the JAK2V617F mutation in the CMPD can be exactly quantified by real-time PCR and were evaluated for their prognostic value in the post transplantation phase and for their utility to plan adoptive immunotherapy in case of molecular relapse. With respect to chimerism, new and very sensitive methods were introduced, for example, quantitative assessment of genetic polymorphisms by real-time PCR, but also methods here are still highly individualized. Only in CML, where SCT focuses now on poor-risk cases or cases of tyrosine kinase inhibitor failure, follow-up schedules are standardized. Standardization of the different diagnostic techniques and of the intervals in the post transplantation period is urgently needed also in other myeloid malignancies and should be focus of future studies.
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PMID:Minimal residual disease diagnostics in myeloid malignancies in the post transplant period. 1858 31


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