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Arthur E Frankel - One of the best experts on this subject based on the ideXlab platform.
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Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies
MDPI AG, 2019Co-Authors: Omar Alkharabsheh, Arthur E FrankelAbstract:Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with Interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile
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in vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to sl 401 an Interleukin 3 receptor targeted biologic agent
Haematologica, 2015Co-Authors: Fanny Angelotdelettre, Arthur E Frankel, Anne Roggy, Baptiste Lamarthee, Estelle Seilles, Sabeha Biichle, Bernard Royer, Eric Deconinck, Eric K Rowinsky, Christopher L BrooksAbstract:Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of Interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the Interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
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activity of sl 401 a targeted therapy directed to Interleukin 3 receptor in blastic plasmacytoid dendritic cell neoplasm patients
Blood, 2014Co-Authors: Arthur E Frankel, Naveen Pemmaraju, Bruno C Medeiros, Francine Garnacheottou, Stephen J Forman, Hetty E Carraway, Olga Frankfurt, Xuezhong A Yang, Marina Konopleva, Fanny AngelotdelettreAbstract:This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the Interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.
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activity and tolerability of sl 401 a targeted therapy directed to the Interleukin 3 receptor on cancer stem cells and tumor bulk as a single agent in patients with advanced hematologic malignancies
Journal of Clinical Oncology, 2013Co-Authors: Arthur E Frankel, Marina Konopleva, Donna E Hogge, David A Rizzieri, Christopher Brooks, Thomas P Cirrito, Steven M Kornblau, Gautam Borthakur, Carol Bivins, Guillermo GarciamaneroAbstract:7029^ Background: SL-401 is a novel biologic targeted therapy directed to the Interleukin-3 receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal he...
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a diphtheria toxin Interleukin 3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from bcr abl positive acute leukemia
Leukemia Research, 2010Co-Authors: Hyun Pyo Kim, Arthur E Frankel, Donna E HoggeAbstract:Abstract Despite initial remissions, most patients with Ph chromosome positive (Ph + ) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the Interleukin-3 receptor (IL-3R) with a diphtheria toxin fusion protein (DT 388 IL3) would improve the effectiveness of TKIs against Ph + AL cells. IL-3R subunits were detected on most Ph + cells and the IC50 for killing of colony forming cell (CFC) with DT 388 IL3 correlated with the level of IL-3Rα subunit by FACS. DT 388 IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G 0 in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT 388 IL3 is much more effective in eliminating Ph + leukemic progenitors that express IL-3R than either agent alone.
Donna E Hogge - One of the best experts on this subject based on the ideXlab platform.
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activity and tolerability of sl 401 a targeted therapy directed to the Interleukin 3 receptor on cancer stem cells and tumor bulk as a single agent in patients with advanced hematologic malignancies
Journal of Clinical Oncology, 2013Co-Authors: Arthur E Frankel, Marina Konopleva, Donna E Hogge, David A Rizzieri, Christopher Brooks, Thomas P Cirrito, Steven M Kornblau, Gautam Borthakur, Carol Bivins, Guillermo GarciamaneroAbstract:7029^ Background: SL-401 is a novel biologic targeted therapy directed to the Interleukin-3 receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal he...
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a diphtheria toxin Interleukin 3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from bcr abl positive acute leukemia
Leukemia Research, 2010Co-Authors: Hyun Pyo Kim, Arthur E Frankel, Donna E HoggeAbstract:Abstract Despite initial remissions, most patients with Ph chromosome positive (Ph + ) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the Interleukin-3 receptor (IL-3R) with a diphtheria toxin fusion protein (DT 388 IL3) would improve the effectiveness of TKIs against Ph + AL cells. IL-3R subunits were detected on most Ph + cells and the IC50 for killing of colony forming cell (CFC) with DT 388 IL3 correlated with the level of IL-3Rα subunit by FACS. DT 388 IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G 0 in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT 388 IL3 is much more effective in eliminating Ph + leukemic progenitors that express IL-3R than either agent alone.
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phase i clinical study of diphtheria toxin Interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia
Leukemia & Lymphoma, 2008Co-Authors: Arthur E Frankel, David A Rizzieri, Jen Sing Liu, Donna E HoggeAbstract:DT388IL3 fusion protein containing the catalytic and translocation domains of diphtheria toxin fused to human Interleukin 3 was administered in an inter-patient dose escalation trial by 15 min i.v. infusions every other day for up to 6 doses to patients with chemo-refractory acute myeloid leukemia (AML) and myelodysplasia (MDS). The maximal tolerated dose was >12.5 µg/kg/dose. Transient grade 3 transaminasemia and grade 2 fevers, chills, hypoalbuminemia, and hypotension occurred. Peak DT388IL3 levels correlated with dose and day of administration but not antibody titer. Anti-DT388IL3 antibodies developed in most patients between day 15 and 30. Of 40 evaluable AML patients, 1 had a CR (8 months) and 1 had PR (3 months). Of 5 MDS patients, 1 had a PR (4 months). Because of the prolonged infusion schedule, many patients failed to receive six doses. DT388IL3 produces remissions in patients with relapsed/refractory AML and MDS with minimal toxicities, and alternate schedules of administration are needed to enh...
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expression of Interleukin 3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin Interleukin 3 fusion protein against malignant progenitors that engraft in immunodeficient mice
Blood, 2006Co-Authors: Leman Yalcintepe, Arthur E Frankel, Donna E HoggeAbstract:The Interleukin-3 receptor (IL-3R) subunits are overexpressed on acute myeloid leukemia (AML) blasts compared with normal hematopoietic cells and are thus potential targets for novel therapeutic agents. Both fluorescence-activated cell sorter (FACS) analysis and quantitative real-time reverse transcription-polymerase chain reaction (QRT-PCR) were used to quantify expression of the IL-3Rα and βc subunits on AML cells. QRT-PCR for both subunits was most predictive of killing of AML colony-forming cells (AML-CFCs) by diphtheria toxin-IL-3 fusion protein (DT388IL3). Among 19 patient samples, the relative level of the IL-3Rα was higher than the IL-3Rβc and highest in CD34+CD38-CD71- cells, enriched for candidate leukemia stem cells, compared with cell fractions depleted of such progenitors. Overall, the amount of IL-3Rβc subunit did not vary among sorted subpopulations. However, expression of both subunits varied by more than 10-fold among different AML samples for all subpopulations studied. The level of IL-3Rβc expression versus glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (set at 1000) ranged from 0.14 to 13.56 in CD34+CD38-CD71- cells from different samples; this value was correlated ( r = .76, P = .05) with the ability of DT388IL3 to kill AML progenitors that engraft in β2-microglobin-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice (n = 7). Thus, quantification of IL-3R subunit expression on AML blasts predicts the effectiveness IL-3R-targeted therapy in killing primitive leukemic progenitors.
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a diphtheria toxin Interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors
Cancer Research, 2002Co-Authors: Michaela Feuringbuske, Arthur E Frankel, Richard L Alexander, Brigitte Gerhard, Donna E HoggeAbstract:The relative cytotoxicity of a diphtheria toxin (DT) human Interleukin 3(IL3) fusion protein (DT(388)IL3) was tested against primitive normal (n = 3)and acute myeloid leukemia (AML) progenitors (n = 7). After 24-h culture with 50 ng/ml DT(388)IL3, the mean percentages of kill of AML colony-forming cells (CFCs), long-term culture-initiating cells (LTC-ICs), and suspension culture-ICs (SC-ICs) were 82% (range, 47-100), 56% (range, 28-91), and 74% (range, 43-87), respectively, with most surviving progenitors being cytogenetically normal. Engraftment of DT(388)IL-3-treated AML cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice followed for 16 weeks was eradicated for two of these samples. In contrast, with normal bone marrow, mean percentages of CFC kill of 49 and 64% were seen with 50 or 250 ng/ml DT(388)IL3, respectively, whereas no significant kills were observed in the LTC-IC and SC-IC assays. The NOD/SCID mouse repopulating cell (RC) frequency in normal BM cells was also not reduced by DT(388)IL3 treatment. In subsequent experiments, NOD/SCID mice that received AML blasts i.v. followed in 24 h by 0.045 microg/g DT(388)IL3 daily i.p. x 5 showed mean percentages of reduction in AML engraftment of 83% (range, 14-100) and 57% (range, 0-98) after 4 and 12 weeks, respectively (n = 6). No evidence of leukemia was detected with two of six AML samples 12 weeks after one 5-day course of DT(388)IL3. Repeating the DT(388)IL3 treatment every 4 weeks enhanced its effectiveness against two additional samples. Thus, DT(388)IL3 kills primitive leukemic progenitors from a proportion of AML patients but shows no significant toxicity against equivalent normal cells.
Christopher L Brooks - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to sl 401 an Interleukin 3 receptor targeted biologic agent
Haematologica, 2015Co-Authors: Fanny Angelotdelettre, Arthur E Frankel, Anne Roggy, Baptiste Lamarthee, Estelle Seilles, Sabeha Biichle, Bernard Royer, Eric Deconinck, Eric K Rowinsky, Christopher L BrooksAbstract:Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of Interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the Interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
Fanny Angelotdelettre - One of the best experts on this subject based on the ideXlab platform.
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in vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to sl 401 an Interleukin 3 receptor targeted biologic agent
Haematologica, 2015Co-Authors: Fanny Angelotdelettre, Arthur E Frankel, Anne Roggy, Baptiste Lamarthee, Estelle Seilles, Sabeha Biichle, Bernard Royer, Eric Deconinck, Eric K Rowinsky, Christopher L BrooksAbstract:Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of Interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the Interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
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activity of sl 401 a targeted therapy directed to Interleukin 3 receptor in blastic plasmacytoid dendritic cell neoplasm patients
Blood, 2014Co-Authors: Arthur E Frankel, Naveen Pemmaraju, Bruno C Medeiros, Francine Garnacheottou, Stephen J Forman, Hetty E Carraway, Olga Frankfurt, Xuezhong A Yang, Marina Konopleva, Fanny AngelotdelettreAbstract:This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the Interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.
Atsushi Miyajima - One of the best experts on this subject based on the ideXlab platform.
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hematopoiesis in mice lacking the entire granulocyte macrophage colony stimulating factor Interleukin 3 Interleukin 5 functions
Blood, 1996Co-Authors: Ryuichi Nishinakamura, Atsushi Miyajima, P J Mee, V L Tybulewicz, Richard MurrayAbstract:Interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 are major hematopoietic cytokines produced by activated T cells and exhibit similar biologic activities by signaling through a common receptor subunit (beta c). Mice lacking beta c show a pulmonary alveolar proteinosis-like disease and reduced numbers of peripheral eosinophils, which are explained by the lack of GM-CSF and IL-5 function, respectively. However, beta c-deficient hematopoietic cells do respond to IL-3 normally, probably through an additional beta subunit of the IL-3 receptor (beta IL3) that is present in the mouse. Thus, almost normal hematopoiesis in beta c-deficient mice may be caused by functional redundancy between IL-3 and GM-CSF. To clarify the role of the entire IL-3/GM-CSF/IL-5 system in hematopoiesis in vivo, we crossed the beta c mutant mice with mice deficient for IL-3 ligand to generate mice lacking the entire IL-3/GM-CSF/IL-5 functions. The double-mutant mice were apparently normal and fertile. The severity of the lung pathology in the beta c/IL-3 double-mutant mice showed normal hemodynamic parameters except for reduced numbers of eosinophils and the lack of eosinophilic response to parasites, which were also found in beta c mutant mice. The immune response of the beta c/IL-3 double-mutant mice to Listeria mono-cytogenes was normal, as was hematopoietic recovery after administration of the cytotoxic drug, 5-fluorouracil. Although it has been believed that IL-3/GM-CSF/IL-5 produced by activated T cells play a major role in expansion of hematopoietic cells in emergency, our results indicate that the entire function of IL-3/GM-CSF/IL-5 is dispensable for hematopoiesis in emergency as well as in the steady state. Thus, there must be an alternative mechanism to produce blood cells in both situations.
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Suppression of Interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation.
The EMBO journal, 1996Co-Authors: Alice L F Mui, Toshio Kitamura, Hiroshi Wakao, T. Kinoshita, Atsushi MiyajimaAbstract:Interleukin-3 (IL3) was shown recently to utilize the transcription factor Stat5, but the genes regulated by this pathway and the biological consequence of Stat5 activation remained to be determined. In order to study the role of Stat5 in IL3 signalling, we constructed a dominant-negative Stat5 protein by C-terminal truncation, and inducibly expressed it in an IL3-dependent cell line. The effect of dominant-negative Stat5 induction on expression of IL3 early response genes was examined, and expression of several genes, including cis, osm and pim-1 was inhibited profoundly. The expression of c-fos was also reduced, but to a lesser extent. While activated Ras alone (though not Stat5 alone) could induce c-fos, maximal expression required the action of both Ras and Stat5. Interestingly, although the membrane-proximal region of the IL3 receptor beta-chain is responsible for both Jak2-Stat5 activation and c-myc induction, c-myc levels were not affected by the dominant-negative Stat5. Thus, the signals directed by this membrane-proximal domain, which is essential for transducing a DNA synthesis signal, can be separated further into Stat5 or c-myc pathways. The net effect of dominant-negative Stat5 expression was partial inhibition of IL3-dependent growth. This provides the first direct evidence that Stat5 is involved in regulation of cell proliferation.
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Interleukin 3 granulocyte macrophage colony stimulating factor and Interleukin 5 transduce signals through two stat5 homologs
The EMBO Journal, 1995Co-Authors: Alice L F Mui, Hiroshi Wakao, A M Ofarrell, N Harada, Atsushi MiyajimaAbstract:Abstract Interleukin-3 (IL-3) is an important regulator of hemopoiesis and considerable effort has been directed towards the study of its mechanism of signal transduction. In this paper, we describe the first molecular identification of a STAT transcription factor that is activated by IL-3. STATs exist in a cytoplasmic, transcriptionally inactive form which, in response to extracellular signals, become tyrosine phosphorylated and translocate to the nucleus where they bind to specific DNA elements. Several of these DNA elements were found which bind proteins in an IL-3-responsive manner. Analysis of these bandshift complexes with available antibodies to the known STATs suggests that IL-3 activates the DNA-binding ability of STAT5, a protein which was originally characterized as a prolactin-responsive transcription factor in sheep. IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF), which share a common signaling receptor subunit with IL-3, also activate STAT5. Unexpectedly, two murine STAT5 homologs, 96% identical to each other at the amino acid level, were isolated and IL-3-dependent GAS binding could be reconstituted in COS cells transfected with IL-3 receptor and either STAT5 cDNA. In IL-3-dependent hemopoietic cells, both forms of STAT5 are expressed and activated in response to IL-3.
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gene for the alpha subunit of the human Interleukin 3 receptor il3ra localized to the x y pseudoautosomal region
American Journal of Human Genetics, 1993Co-Authors: Athena Milatovich, Atsushi Miyajima, Toshio Kitamura, Uta FranckeAbstract:Interleukin-3 (IL3) and granulocyte/macrophage colony-stimulating factor (CSF2) stimulate proliferation and differentiation of various hemopoietic cell types. As is characteristic of the cytokine receptor family, the receptors for these proteins comprise [alpha]- and [beta]-subunits. While IL3 and CSF2 receptors each have unique [alpha]-subunits, they share a common [beta]-subunit. By Southern analysis of somatic cell hybrid panels, pulsed-field gel electrophoresis (PFGE), and fluorescence chromosomal in situ hybridization, the authors have mapped the cloned sequence for the IL3 receptor [alpha] (IL3RA) to the X-Y pseudoautosomal region at bands Xp22.3 and Yp11.3, near the gene for the [alpha]-subunit of the CSF2 receptor (CSF2RA). The CSF2RA and IL3RA genes are so close that their order could not be determined by two-color interphase in situ hybridization. They share PFGE fragments generated by different restriction enzymes down to the 50-100-kb size range. Pseudoautosomal inheritance was demonstrated by an EcoRI RFLP detected with the IL3RA cDNA probe. 47 refs., 6 figs.