RESUMEN
Acute promyelocytic leukemia (APL) is characterized by a series of retinoic acid receptor (RAR) fusion genes that lead to the dysregulation of RAR signaling and onset of APL. PML-RARA is the most common fusion generated from t(15;17)(q24;q21). In addition, the reciprocal fusion RARA-PML is present in over 80% of t(15;17) APL cases. The bcr3 types of RARA-PML and RARA-PLZF in particular are reciprocal fusions that contribute to leukemogenesis. Here, we report a variant APL case with t(11;17;15)(q13;q21.2;q24.1). Massive parallel sequencing of patient RNA detected the novel fusion transcripts RARA-SNX15 and SNX15-LINC02255 along with the bcr3 type of PML-RARA. Genetic analysis revealed that RARA-SNX15L is an in-frame fusion due to intron retention caused by RNA mis-splicing. RARA-SNX15L consisted mainly of SNX15 domains, including the Phox-homology domain, which has a critical role in protein-protein interactions among sorting nexins and with other partners. Co-immunoprecipitation analysis revealed that RARA-SNX15L is directly associated with SNX15 and with itself. Further studies are needed to evaluate the biological significance of RARA-SNX15L in APL. In conclusion, this is the first report of APL with a complex chromosomal rearrangement involving SNX15.
Asunto(s)
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/genética , Receptores de Ácido Retinoico/genética , Fusión Génica , Intrones , ARN , Translocación Genética , Proteínas de Fusión Oncogénica/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 15/genéticaRESUMEN
Anemia, a frequently occurring condition in older patients, has no standard definition; however, in most studies, it is defined as hemoglobin level <12 and <13 g/dL in women and men, respectively. Approximately 10% of older adults living in the community have anemia. The prevalence of anemia is significantly correlated with advanced age and male sex. Anemia is associated with falls, frailty and other negative outcomes, including early mortality. However, there remains little consensus regarding whether anemia treatment favorably affects these adverse outcomes. Therefore, this article reviews the prevalence of anemia, and provides updates on its common causes and treatments in older adults. While excluding well-established hematopoietic diseases, the etiology of anemia in older adults has been grouped into four categories: (i) nutritional deficiency; (ii) inflammation; (iii) clonal hematopoiesis; and (iv) "unexplained anemia," when there is no clear mechanism to account for the anemia. Recently, clonal leukocytes were detected in a considerable number of older individuals. The number of somatic mutations in blood leukocytes increases with age; however, single mutations of DNMT3A, TET2 and ASXL1 are not correlated with the presence of unexplained anemia in older adults. With an increased understanding of anemia etiology and the availability of innovative anti-anemic drugs, future studies that evaluate the causes and benefits of treatment are required. Geriatr Gerontol Int 2021; 21: 549-554.
Asunto(s)
Anemia , Fragilidad , Desnutrición , Anciano , Femenino , Hematopoyesis , Humanos , Inflamación , Masculino , PrevalenciaRESUMEN
The helix-sense reversal of poly(ß-phenylpropyl l-aspartate) (3PLA) in the solid state was studied by synchrotron wide-angle X-ray diffraction and small-angle X-ray scattering. The direct determination of the characteristic helical pitch before and after the transition revealed that the transition takes place reversibly between the two α-helices having opposite screw-sense during the heating and cooling cycle. While the hexagonal packing remains unaltered, the helix-sense inversion causes discontinuous changes in the molecular arrangement and, by extension, the crystalline dimension. In this study, another transition was detected at a higher temperature from the left-handed α-helix to the π-helix, the molecular chirality being unaffected.
Asunto(s)
Ácido Aspártico/química , Polímeros/química , Ácido Aspártico/síntesis química , Estructura Molecular , Polímeros/síntesis química , Sincrotrones , Difracción de Rayos XRESUMEN
Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , ADN sin Sentido/genética , Fusión Génica/genética , Factor Estimulante de Colonias de Granulocitos/farmacología , Leucemia Mieloide Aguda/genética , Receptores de Ácido Kaínico/genética , Eliminación de Secuencia/genética , Translocación Genética/genética , Proliferación Celular/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , ARN Mensajero/genética , Receptores de Factor Estimulante de Colonias de Granulocito/biosíntesis , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Receptor de Ácido Kaínico GluK2RESUMEN
T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic cardiovascular disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-myc, which were reversed by a proteasome inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by AKT inhibition and GSK3 dephosphorylation. PI3K/AKT inhibitors mimicked PNT, suggesting that PI3K/AKT signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients.
Asunto(s)
Antineoplásicos/farmacología , Ciclina D2/metabolismo , Mesilato de Imatinib/farmacología , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Piridazinas/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Ciclina D2/genética , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leupeptinas/farmacología , Compuestos Macrocíclicos/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteína Fosfatasa 2/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Wortmanina/farmacologíaRESUMEN
In recent years, bioremediation has been used as an effective technique for the cleaning of polluted sites. However, bioremediation treatment efficacy varies considerably; thus, characterization of indigenous pollutant-degrading soil microorganisms and assessment of the changes in microbial composition by pollutants are essential for designing efficient bioremediation methods. In this study, an ecological impact evaluation method that is cost-efficient and has low contamination risk was developed to assess the indigenous microbial composition. An "in situ microcosm" was constructed using a porous ceramic arrowhead. Phenol, a common environmental pollutant, was used to assess the evaluation efficacy of this method. Our data showed that phenol gradually percolated into the soil adjacent to the arrowhead and stimulated unique indigenous microorganisms (Bacillus sp., Streptomyces sp., and Cupriavidus sp.). Furthermore, the arrowhead approach enabled efficient evaluation of the ecological impact of phenol on soil microorganisms. Thus, the arrowhead method will contribute to the development of bioremediation methods.
Asunto(s)
Biodegradación Ambiental , Contaminantes del Suelo/química , Suelo/química , Microbiología del SueloRESUMEN
Imatinib (IMT), a specific tyrosine kinase inhibitor (TKI), has drastically changed the treatment strategy for Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia). However, TKI resistance remains a serious problem for patient prognosis. Here, a Ph+ ALL cell line NphA2 and the IMT-resistant subline NphA2/STIR were analyzed to identify a potential novel treatment strategy. We also examined other Ph+ ALL cells, MR87 and its IMT-resistant subline, MR87/STIR. IMT induced apoptosis of NphA2 and MR87 but had no effect on resistant sublines. Increased phosphorylated ERK and BCL2, but not BCL-XL, were observed in NphA2/STIR compared with NphA2. NphA2/STIR but not NphA2 was moderately sensitive to U0126, an ERK inhibitor. Interestingly, SP600125, a JNK inhibitor, was potent in cell growth inhibition and apoptosis induction of both parental and IMT-resistant NphA2 and MR87 cells. Moreover, NphA2 and MR87 and their IMT-resistant sublines were sensitive to ABT-199, a specific BCL2 inhibitor. The combination of SP600125 and ABT-199 synergistically suppressed both parental and IMT-resistant cells, including one with T315I mutation, suggesting that Ph+ ALL exhibits high sensitivity to ABT-199 and SP600125 regardless of TKI resistance. This combination might be a possible therapeutic strategy for Ph+ ALL in the future.
RESUMEN
Variant chromosomal translocations associated with t(8;21) are observed in 3-4% of acute myeloid leukemia (AML) cases with a RUNX1-RUNX1T1 fusion gene. However, the molecular events that occur in variants of t(8;21) are not well characterized. In the present study, we report genetic features of a variant three-way translocation of t(8;12;21)(q22;p11;q22) in a patient with AML. In this patient, leukemia cells lacked azurophilic granules, which does not correspond with the classic features of t(8;21). RNA-seq analysis revealed that TM7SF3 at 12p11 was fused to VPS13B at 8q22 and VPS13B to RUNX1, in addition to RUNX1-RUNX1T1. VPS13B was located near RUNX1T1 and both were localized at the same chromosomal bands. The reading frames of TM7SF3 and VPS13B did not match to those of VPS13B and RUNX1, respectively. Disruption of VPS13B causes Cohen syndrome, which presents intermittent neutropenia with a left-shifted granulopoiesis in the bone marrow. Disruption of VPS13B may thus cause the unusual features of RUNX1-RUNX1T1 leukemia. Our case indicates that rearrangement of VPS13B may be additional genetic events in variant t(8;21).
Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Dedos/anomalías , Reordenamiento Génico/genética , Discapacidad Intelectual/genética , Leucemia Mieloide Aguda/genética , Microcefalia/genética , Hipotonía Muscular/genética , Miopía/genética , Obesidad/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Translocación Genética/genética , Proteínas de Transporte Vesicular/genética , Discapacidades del Desarrollo/genética , Femenino , Humanos , Persona de Mediana Edad , Degeneración RetinianaRESUMEN
The soluble protein fraction of the extremely halophilic archaeon Haloarcula japonica exhibits substantial inorganic pyrophosphate (PPi) hydrolysis activity in the presence of 2-4 M NaCl (Wakai et al, J Biol Chem 288:29247-29251, 2013), which provides high ionic strength (2-4). In this study, much higher PPi hydrolysis activity was unexpectedly detected, even with 0 M NaCl in the presence of 100-200 mM MgSO4, providing a much lower ionic strength of 0.4-0.8, in the same protein fraction. Na+ and Mg2+ ions were required for activity under high and low ionic strength conditions, respectively. A recombinant H. japonica pyrophosphatase (HjPPase) exhibited PPi hydrolysis activity with the same broad ionic strength range, indicating that the activity associated with such a broad ionic strength range could be attributed to a single enzyme. Thus, we concluded that the broad ionic strength range of HjPPase may contribute to adaptation for both Na+ and Mg2+ which are abundant but variable in the unstable living environments of H. japonica.
Asunto(s)
Proteínas Arqueales/metabolismo , Difosfatos/metabolismo , Haloarcula/enzimología , Pirofosfatasas/metabolismo , Proteínas Arqueales/química , Ambientes Extremos , Haloarcula/metabolismo , Concentración Osmolar , Pirofosfatasas/química , SalinidadAsunto(s)
Comunicación Celular , Leucemia Mieloide Aguda/patología , Células del Estroma/fisiología , Vía de Señalización Wnt/fisiología , Amidas/farmacología , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/fisiología , Comunicación Celular/efectos de los fármacos , Comunicación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Piridinas/farmacología , Células del Estroma/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
ETV6, which encodes an ETS family transcription factor, is frequently rearranged in human leukemias. We show here that a patient with acute myeloid leukemia with t(7;11)(p15;p15) gained, at the time of relapse, t(11;12)(q12.1;p13) with a split ETV6 FISH signal. Using 3'-RACE PCR analysis, we found that ETV6 was fused to LPXN at 11q12.1, which encodes leupaxin. ETV6-LPXN, an in-frame fusion between exon 4 of ETV6 and exon 2 of LPXN, did not transform the interleukin-3-dependent 32D myeloid cell line to cytokine independence; however, an enhanced proliferative response was observed when these cells were treated with G-CSF without inhibition of granulocytic differentiation. The 32D and human leukemia cell lines each transduced with ETV6-LPXN showed enhanced migration towards the chemokine CXCL12. We show here for the first time that LPXN is a fusion partner of ETV6 and present evidence indicating that ETV6-LPXN plays a crucial role in leukemia progression through enhancing the response to G-CSF and CXCL12.
Asunto(s)
Moléculas de Adhesión Celular/genética , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Fosfoproteínas/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Translocación Genética , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 12 , Fusión Génica , Humanos , Masculino , Proteína ETS de Variante de Translocación 6RESUMEN
DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5'-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5'- and 3'-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5'-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML.
Asunto(s)
Cromosomas Humanos , Colágeno Tipo XII/genética , Leucemia Mieloide Aguda/genética , Proteínas de Complejo Poro Nuclear/genética , Translocación Genética , Proteína de Unión al GTP rac1/genética , Adulto , Humanos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARN , Cariotipificación EspectralRESUMEN
The BCR-ABL1 fusion gene is the molecular marker of chronic myeloid leukemia (CML). The e19a2 transcript is a rare variant associated with various clinical presentations and courses of CML. We herein present a case of e19a2-positive CML who was intolerant to initial treatment with imatinib and successfully responded to subsequent nilotinib therapy. She achieved a major molecular response and has since be able to sustain it. According to the literature, achieved molecular response by imatinib monotherapy has not yet been reported in e19a2-positive CML patients. Second generation tyrosine kinase inhibitors may therefore be a more effective treatment for e19a2-positive CML patients.
Asunto(s)
Benzamidas/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Resistencia a Antineoplásicos/genética , Femenino , Proteínas de Fusión bcr-abl/efectos de los fármacos , Humanos , Mesilato de Imatinib , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
We have developed a new method for determining ethanolamine plasmalogen contents in marine invertebrates. This quantification method involves derivatization of ethanolamine glycerophospholipid (EtnGpl) subclasses, alkenylacyl (plasmalogen), diacyl, and alkylacyl subclasses, by enzyme treatment and acetylation, followed by separation and detection by high-performance liquid chromatography (HPLC) with evaporative light-scattering detection (ELSD). This method enabled complete separation of the subclasses, and the limit of detection for plasmalogen was 200 ng (260 pmol). The peak area of plasmalogen by ELSD was unaffected by the degree of unsaturated fatty acids in EtnGpl, in contrast to ultraviolet (UV) detection. Thus, this method enables accurate determination of plasmalogen contents in various species containing marine products possessing abundant polyunsaturated fatty acids (PUFA). The method developed here was applied to marine invertebrates available in Japan. The examined marine invertebrates showed a wide range of plasmalogen contents ranging from 19 to 504 µmol/100 g wet wt. The plasmalogen levels in samples except those of class Cephalopoda and Crustacea were more than 60 mol% of EtnGpl.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Invertebrados/química , Fosfatidiletanolaminas/análisis , Plasmalógenos/análisis , Animales , Organismos Acuáticos , Japón , Luz , Fosfatidiletanolaminas/aislamiento & purificación , Plasmalógenos/aislamiento & purificación , Dispersión de RadiaciónRESUMEN
Varicella, characterized by a vesicular rash, occurs primarily in young children. Although older individuals can also be affected or vaccinated, outbreaks among adults are rare. We investigated a small outbreak of varicella in B-cell lymphoma patients for elucidation of risk factor of the disease. We experienced four cases of varicella after an index herpes zoster case. All varicella cases were confirmed varicella zoster virus (VZV) infection by PCR. All varicella cases occurred in diffuse large B-cell lymphoma patients receiving rituximab-containing chemotherapy. On the other hand, only three of the 18 non-varicella patients in the same room were receiving rituximab-containing chemotherapy (P = 0.005). All varicella patients had detectable serum anti-varicella zoster virus IgG antibodies before chemotherapy. Even in the presence of neutralizing antibodies to the virus, lymphoma patients treated with rituximab-containing chemotherapy can possibly become re-infected with varicella. These findings suggest that zoster patients should be strictly isolated in hematology and oncology ward, and prophylactic acyclovir should be considered for such patients when exposed to zoster/varicella.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antineoplásicos/efectos adversos , Varicela/etiología , Infección Hospitalaria/virología , Brotes de Enfermedades , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/virología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Varicela/virología , Infección Hospitalaria/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , RituximabRESUMEN
Taxol was originally isolated from the yew Taxus brevifolia. Because taxol inhibits the depolymerization of microtubules, the presence of a self-resistance mechanism in Taxus spp. was hypothesized. The cloning of the cDNA for alpha and beta tubulins from Taxus cuspidata and those from the human embryonic kidney cell line HEK293T revealed that the (26)Asp, (359)Arg, and (361)Leu residues in the human beta tubulin, which are important for taxol binding, were replaced with Glu, Trp, and Met in the beta tubulin of T. cuspidata, respectively. The microtubule assembly of the recombinant alpha and beta tubulins was monitored turbidimetrically, and the results clearly demonstrated that the microtubule from T. cuspidata is less sensitive to taxol than that from HEK293T cells. The Taxus microtubule composed of the wild-type alpha tubulin and the beta tubulin with the E26D mutation restored the sensitivity to taxol. We thus postulated that the mutation identified in the beta tubulin of T. cuspidata plays a role in the self-resistance of this species against taxol.
Asunto(s)
Regulación de la Expresión Génica de las Plantas , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Paclitaxel/farmacología , Taxus/química , Taxus/genética , Tubulina (Proteína)/genética , Sustitución de Aminoácidos , Clonación Molecular , Secuencia de Consenso , Células HEK293 , Humanos , Estructura Molecular , Unión Proteica/efectos de los fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Taxus/efectos de los fármacos , Taxus/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologíaRESUMEN
The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics.
Asunto(s)
Neoplasias/genética , Proteínas del Grupo Polycomb/genética , Proteínas Proto-Oncogénicas/genética , Ciclina B/genética , Proteínas de Unión al ADN/genética , Femenino , Genes Supresores de Tumor , Mutación de Línea Germinal , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Masculino , Proteínas Represoras/genética , Factores de Transcripción/genéticaRESUMEN
Patients in the chronic phase (CP) of chronic myelogenous leukemia (CML) have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC) phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt.) AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.
Asunto(s)
Crisis Blástica/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Fenotipo , Animales , Crisis Blástica/patología , Western Blotting , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Análisis Mutacional de ADN , Cartilla de ADN/genética , Citometría de Flujo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Ratones Endogámicos C57BL , Mutación Missense/genética , Plásmidos/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Patients suffering from bone defects are often treated with autologous bone transplants, but this therapy can cause many complications. New approaches are therefore needed to improve treatment for bone defects, and stem cell therapy presents an exciting alternative approach. Although extensive evidence from basic studies using stem cells has been reported, few clinical applications using stem cells for bone tissue engineering have been developed. We investigated whether injectable tissue-engineered bone (TEB) composed of mesenchymal stem cells (MSCs) and platelet-rich plasma was able to regenerate functional bone in alveolar deficiencies. We performed these studies in animals and subsequently carried out large-scale clinical studies in patients with long-term follow-up; these showed good bone formation using minimally invasive MSC transplantation. All patients exhibited significantly improved bone volume with no side effects. Newly formed bone areas at 3 months were significantly increased over the preoperation baseline (p < .001) and reached levels equivalent to that of native bone. No significant bone resorption occurred during long-term follow-up. Injectable TEB restored masticatory function in patients. This novel clinical approach represents an effective therapeutic utilization of bone tissue engineering.
Asunto(s)
Huesos/fisiología , Huesos/cirugía , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/fisiología , Ingeniería de Tejidos , Adulto , Anciano , Animales , Regeneración Ósea/fisiología , Perros , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Persona de Mediana Edad , Modelos Animales , Medicina Regenerativa/métodos , Adulto JovenRESUMEN
The RUNX1 locus, which encodes a transcription factor that is essential for normal hematopoiesis, is a frequent location of chromosomal rearrangements in human hematological malignancies. We report the case of a 78-year-old man with acute myeloid leukemia (AML), M1 subtype (French-American-British classification), with a t(11;21)(p14;q22). Fluorescence in situ hybridization showed a split signal for RUNX1, which indicated that RUNX1 was involved in this translocation. Using 3'-rapid amplification of cDNA ends and reverse transcription-polymerase chain reaction analyses, we found that RUNX1 was fused to C11orf41 on 11p14 and detected two in-frame C11orf41-RUNX1 fusion transcripts. One was a fusion between exon 5 of RUNX1 and exon 13 of C11orf41, and the other was between exon 6 of RUNX1 and exon 13 of C11orf41. This suggested that the RUNX1 breakpoint was in intron 6 and had generated alternative fusion splice variants. A reciprocal C11orf41-RUNX1 fusion was not detected. Thus, we identified C11orf41 as a novel fusion partner of RUNX1 in AML.