Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute megakaryoblastic leukemia (AMkL) is a newly defined acute leukemia in which the differentiation of proliferating blasts is arrested at the megakaryocytic precursor stage. In order to clarify whether a target cell of leukemic transformation in AMkL is a cell committed to megakaryocytic lineage, or a multipotential stem cell, we examined AMkL patients with regard to: a) the presence of myelodyplastic features in residual erythroid and granulocytic cells, b) coexistence of myeloperoxidase (MPO)-positive blasts with megakaryoblasts, and c) the presence of the same chromosomal abnormality in erythroid and granuloid colony-forming cells as seen in megakaryoblasts. Regarding the former two items, results were compared with those from megakaryoblastic crisis of chronic myelocytic leukemia (CML-MkBC) and transient myeloproliferative disorder in Down syndrome (DS-TMD), which are thought to be multipotential stem cell disorders. Among 18 patients with AMkL, three, all complicating myelofibrosis, had marked myelodysplastic changes of erythroid series and/or granulocytic series. In 4 out of 7 patients with CML-MkBC, 5 out of 8 patients with DS-TMD, and 7 out of 18 patients with AMkL, MPO-positive blasts, even though rare, were observed in addition to PPO-positive blasts. All except one of these patients with AMkL also showed complicating myelofibrosis. In one case of AMkL with myelofibrosis, chromosomal analysis of cultured cells of individual colonies revealed that all the analysable metaphases from both CFU-GM and BFU-E had the same chromosomal abnormality as megakaryoblasts. This study has clarified that a considerable proportion of AMkL cases, particularly those with complicating myelofibrosis or showing acute myelofibrosis, arise against the background of a multipotential stem cell disorder, even if blasts are exclusively megakaryocytic in phenotype.
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PMID:Target cell of leukemic transformation in acute megakaryoblastic leukemia. 216 21

Using the megakaryocytic leukemia cell lines, K-562 and CMK established from a Down's patient with acute megakaryoblastic leukemia, we studied the changes of antigen expression, cytosolic Ca2+ mobilization, thromboxane (TX) A2 formation and gene expression during megakaryocyte differentiation. We found that thrombospondin synthesis and platelet factor (PF)-4 gene expression were specific for mature megakaryoblasts, whereas collagen unresponsiveness and prostaglandin E1-induced Ca2+ mobilization were noted in immature megakaryoblasts alone. This experiment shows that functional and genetic analysis are useful for characterizing the leukemic megakaryoblastic cells. We analyzed the clinical, hematologic and genetic features of 4 patients with M7, and acute megakaryoblastic transformation of CML, MDS and essential thrombocythemia. In two patients, prednisolone and 6-MP were effective in cytoreduction. In 3 patients with increased platelet counts, normal CFU-Meg formation, the megakaryoblasts with platelet production, or the coexistence of immature megakaryoblasts with mature megakaryocytes were observed, thus indicating that some megakaryoblastic leukemia cells still have the capacity of differentiation. One patient had megakaryoblastic cells with PF-4 gene expression. These clinical findings suggest that the megakaryoblastic leukemia could not be characterized as usual leukemia and a more sensitive marker is required to differentiate leukemic megakaryoblasts from normal megakaryoblasts.
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PMID:[Megakaryocytic leukemia cell lines and megakaryocytic leukemia]. 238 Oct 77

Using DNA staining with highly stable osmium-ammine-B, the blasts of AMKL were observed under an electron microscope, in comparison with AML, ALL, CML-MK crisis and TMD. The DNA within the nucleus of the megakaryoblasts was observed as a high electron-density substance and tended to be uniformly dispersed within the nucleus. DNA, associated with nucleoli, could be roughly divided in four types based on the presence or absence of peri-nucleolar clumps and intra-nucleolar clumps. In cases of AMKL, we often observed a type that did not have peri-nucleolar DNA clumps but did have DNA flecks within the nucleoli. By analytical evaluation there were no differences among cells from several subtypes of megakaryocytic leukemia, such as AMKL in children with Down's syndrome, AMKL in children without Down's syndrome, AMKL in adults, and CML-MK crisis. The DNA distribution of TMD blasts, which were self-limited and not malignant, resembled that of AMKL blasts.
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PMID:Ultrastructural investigation of DNA in megakaryoblastic leukemia by using osmium-ammine-B: comparison with several types of leukemia. 826 56

Bcr-Abl, the product of the protooncogene bcr-abl, is a constitutively active protein-tyrosine kinase that is highly expressed in chronic myelogenous leukemia and in acute myeloid leukemia cells. Because Bcr-Abl is known to provide mitogenic signals through suppression of apoptosis, we investigated the effect of this oncogene product on signaling by tumor necrosis factor (TNF), a proapoptotic cytokine. We used a bcr-abl-deficient human megakaryocytic leukemia cell line MO7E and an isogenic MBA cell line stably transfected with bcr-abl. Electrophoretic mobility shift assay revealed that TNF activated the nuclear transcription factor NF-kappaB in MO7E cells but not in MBA cells. The impaired NF-kappaB activation in Bcr-Abl-expressing cells was not due to absence of the NF-kappaB proteins p65, p50, or p100 or of IkappaBalpha or IkappaBbeta. Okadaic acid-induced NF-kappaB activation was unaffected by Bcr-Abl expression. TNF induced IkappaBalpha phosphorylation and degradation in MO7E cells but not in MBA cells. The suppression of TNF-induced NF-kappaB activation by Bcr-Abl was not restricted to MBA cells, because ectopic expression of Bcr-Abl in human acute myeloid leukemia HL-60 cells also blocked TNF-induced NF-kappaB activation. When examined for the TNF receptors by the radioreceptor assay, flow cytometry, or Western blot analysis, we found that Bcr-Abl expression down-regulated the expression of the TNF receptors. The RNase protection assay and Northern blot analysis revealed the transcriptional down-regulation of the TNF receptor by Bcr-Abl protein. Overall, these results indicate that ectopic expression of Bcr-Abl interferes with the TNF signaling pathway through the down-regulation of TNF receptors.
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PMID:Ectopic expression of protein-tyrosine kinase Bcr-Abl suppresses tumor necrosis factor (TNF)-induced NF-kappa B activation and IkappaBalpha phosphorylation. Relationship with down-regulation of TNF receptors. 1206 Jun 65

Acute megakaryocytic leukemia is a rare form of acute myelogenous leukemia and may occur either de novo or by transformation of a preexisting myelodysplastic or myeloproliferative process including blast crisis of chronic myeloid leukemia (CML). Megakaryocytic blast crisis as the presenting manifestation of CML is extremely rare. We describe such a patient with no prior hematologic disease who presented with acute megakaryoblastic leukemia and extramedullary involvement, in whom the leukemic cells carried the BCR-ABL1 translocation as part of a complex karyotype. Using targeted sequential fluorescence in situ hybridization (T-FISH) technique, we detected two copies of BCR-ABL1 fusion gene in the leukemic blasts while the neutrophils carried a single copy of BCR-ABL1 fusion gene, thereby proving the origin of the megakaryoblastic leukemia from a previously undiagnosed CML clone. Blast crisis as a presenting manifestation of CML is rare and detecting clonal evolution of acute leukemia by specialized cytogenetic techniques may have important diagnostic and therapeutic implications.
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PMID:Megakaryocytic blast crisis as a presenting manifestation of chronic myeloid leukemia. 2037 69

Patients with chronic myeloid leukemia (CML) infrequently present in blast crisis (BC). While most BC are of myeloid origin, megakaryocytic BC is rare, especially at the time of CML diagnosis. We describe the first pediatric patient presenting with megakaryocytic leukemia and having BCR-ABL1 translocation as the single chromosomal abnormality. Clinical features were more suggestive of CML in megakaryocytic blast crisis than Philadelphia chromosome positive de novo AML. The patient was treated with AML-directed chemotherapy and imatinib mesylate followed by umbilical cord blood stem cell transplantation. The patient was in complete molecular response 16 months after stem cell transplantation.
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PMID:Megakaryocytic blast crisis at presentation in a pediatric patient with chronic myeloid leukemia. 2023 13

RNA binding motif protein 15 (RBM15) was originally described as a 5' translocation partner of the MAL gene in t(1;22)(p13;q13)infant acute megakaryocytic leukemia. Although previous investigations have shown that Rbm15 has broad regulatory effects within murine hematopoiesis through modulating Notch-induced transcriptional activation, which plays key roles in leukemogenesis, it is not clear what the functions of RBM15 are in the regulation of hematological malignancies. In the present study, we show that RBM15 expression was significantly increased in patients with blast-crisis chronic myelogenous leukemia (CML) compared with chronic-phase or accelerated-phase disease by real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. To further elucidate the role of RBM15 in CML, we introduced RBM15 small interfering RNA (siRNA) using pSUPER into CML cells. Fluorescence activated cell sorting (FACS), real-time RT-PCR and Western blot were used to study changes in RBM15 expression levels in transduced cells by comparing with control cells. Decreasing RBM15 levels with RNA interference could inhibit the growth and proliferation, block the cell cycle and induce apoptosis in CML cells. Knockdown of RBM15 may also act to inhibit clonogenicity and induce differentiation of CML cells along the myeloid lineage. Our studies also show that the effects of RBM15 on CML cells may be mediated, at least in part, via its effect on Notch signaling. These findings demonstrate that RBM15 does indeed play a critical role in the survival of CML cells, which may have potential application in designing molecular therapies for CML treatment.
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PMID:Biological effects of decreasing RBM15 on chronic myelogenous leukemia cells. 2249 98

Acute megakaryocytic leukaemia (AMeL) is a rare subtype of acute myeloid leukaemia, which can be frequently misdiagnosed as acute myelofibrosis or myelosclerosis [1]. Chronic myeloid leukaemia (CML) presenting primarily as megakaryocytic blast crisis is very rare, with very few case reports published to date [2, 3]. This case report describes a 36-year-old woman who presented with anaemia and massive splenomegaly with peripheral blood and bone marrow showing features of AMeL. Reverse transcriptase polymerase chain reaction and gel-electrophoretic study of peripheral blood leucocytes demonstrated breakpoint cluster region-Abelson oncogene translocation encoding for p210 fusion protein. Megakaryocytic blast crisis as the primary presentation of CML is very rare and requires clinical correlation and additional cytogenetic studies to determine the diagnosis.
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PMID:A case of chronic myeloid leukaemia presenting as megakaryocytic blast crisis (AML M7). 2428 46

Megakaryocytes (MKs) are one of the few cell types that become polyploid; however, the mechanisms by which these cells are designated to become polyploid are not fully understood. In this investigation, we successfully established two relatively synchronous polyploid cell models by inducing Dami and CMK cells with SP600125. We found that SP600125 induced the polyploidization of Dami and CMK cells, concomitant with the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) at Thr421/Ser424 and dephosphorylation at Thr389. The polyploidization was partially blocked by H-89, a cAMP-dependent protein kinase (PKA) inhibitor, through direct binding to S6K1, leading to dephosphorylation at Thr421/Ser424 and phosphorylation at Thr389, independent of PKA. Overexpression of a rapamycin-resistant mutant of S6K1 further enhanced the inhibitory effect of LY294002 on the SP600125-induced polyploidization of Dami and CMK cells. SP600125 also induced the polyploidization of Meg-01 cells, which are derived from a patient with chronic myelogenous leukemia, without causing a significant change in S6K1 phosphorylation. Additionally, SP600125 induced the polyploidization of HEL cells, which are derived from a patient with erythroleukemia, and phosphorylation at Thr389 of S6K1 was detected. However, the polyploidization of both Meg-01 cells and HEL cells as a result of SP600125 treatment was lower than that of SP600125-induced Dami and CMK cells, and it was not blocked by H-89 despite the increased phosphorylation of S6K1 at Thr389 in both cell lines in response to H-89. Given that the Dami and CMK cell lines were derived from patients with acute megakaryocytic leukemia (AMKL) and expressed high levels of platelet-specific antigens, our data suggested that SP600125-induced polyploidization is cell-type specific, that these cell lines were more differentiated, and that phosphorylation at Thr421/Ser424 and dephosphorylation at Thr389 of S6K1 may play an important role in the SP600125-induced polyploidization of these cell lines synergistically with other signaling pathways.
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PMID:Phosphorylation of ribosomal protein S6 kinase 1 at Thr421/Ser424 and dephosphorylation at Thr389 regulates SP600125-induced polyploidization of megakaryocytic cell lines. 2548 32