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OBJECTIVE: Body composition assessment derived from cross-sectional imaging has shown promising results as a prognostic biomarker in several tumor entities. Our aim was to analyze the role of low skeletal muscle mass (LSMM) and fat areas for prognosis of dose-limiting toxicity (DLT) and treatment response in patients with primary central nervous system lymphoma (PCNSL). METHODS: Overall, 61 patients (29 female patients, 47.5%) with a mean age of 63.8 ± 12.2 years, range 23-81 years, were identified in the data base between 2012 and 2020 with sufficient clinical and imaging data. Body composition assessment, comprising LSMM and visceral and subcutaneous fat areas, was performed on one axial slice on L3-height derived from staging computed tomography (CT) images. DLT was assessed during chemotherapy in clinical routine. Objective response rate (ORR) was measured on following magnetic resonance images of the head accordingly to the Cheson criteria. RESULTS: Twenty-eight patients had DLT (45.9%). Regression analysis revealed that LSMM was associated with objective response, OR = 5.19 (95% CI 1.35-19.94, p = 0.02) (univariable regression), and OR = 4.23 (95% CI 1.03- 17.38, p = 0.046) (multivariable regression). None of the body composition parameters could predict DLT. Patients with normal visceral to subcutaneous ratio (VSR) could be treated with more chemotherapy cycles compared to patients with high VSR (mean, 4.25 vs 2.94, p = 0.03). Patients with ORR had higher muscle density values compared to patients with stable and/or progressive disease (34.46 ± vs 28.18 ± HU, p = 0.02). CONCLUSIONS: LSMM is strongly associated with objective response in patients with PCNSL. Body composition parameters cannot predict DLT. CLINICAL RELEVANCE STATEMENT: Low skeletal muscle mass on computed tomography (CT) is an independent prognostic factor of poor treatment response in central nervous system lymphoma. Analysis of the skeletal musculature on staging CT should be implemented into the clinical routine in this tumor entity. KEY POINTS: ⢠Low skeletal muscle mass is strongly associated with the objective response rate. ⢠No body composition parameters could predict dose-limiting toxicity.
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Linfoma , Neoplasias , Sarcopenia , Humanos , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Sarcopenia/patología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Pronóstico , Composición Corporal , Tomografía Computarizada por Rayos X , Neoplasias/patología , Sistema Nervioso Central/patología , Linfoma/diagnóstico por imagen , Linfoma/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.
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Quinasas Janus , Policitemia Vera , Humanos , Hidroxiurea/uso terapéutico , Inutilidad Médica , Nitrilos/uso terapéutico , Policitemia Vera/diagnóstico , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Pirimidinas/uso terapéutico , Quinasas Janus/uso terapéuticoAsunto(s)
Agammaglobulinemia Tirosina Quinasa/metabolismo , Quimiocina CXCL12/metabolismo , Quimiotaxis , Regulación de la Expresión Génica , Janus Quinasa 2/metabolismo , Mutación , Células Progenitoras Mieloides/fisiología , Agammaglobulinemia Tirosina Quinasa/genética , Movimiento Celular , Células Cultivadas , Quimiocina CXCL12/genética , Humanos , Janus Quinasa 2/genética , Células Progenitoras Mieloides/citología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfolipasa C gamma/genética , Fosfolipasa C gamma/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for several hematological neoplasms. This study aimed to assess the parameters of body composition as predictors of post-transplant overall survival (OS) and adverse events in patients with leukemia, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). METHODS: This was a retrospective study of 122 adult patients who underwent their first allo-HSCT. The CT-based semi-automated measurement of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), visceral-to-subcutaneous fat ratio (VSR), sarcopenia in terms of skeletal muscle index (SMI), and myosteatosis based on the skeletal muscle radiation attenuation (SM-RA) was performed. Cox regression analysis was used to assess the association of body composition parameters with OS. RESULTS: In the univariate analysis, low SAT and myosteatosis were associated with lower OS (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.16-3.51, p = 0.01) and (HR 2.50, 95% CI 1.48-4.25, p =< 0.001), respectively. This association remained significant after adjusting for relevant covariates, with HR 2.32, 95% CI 1.23-4.38, p = 0.01 and HR 2.86, 95% CI 1.51-5.43, p =< 0.001, respectively. On the contrary, VAT, VSR, sarcopenia, and sarcopenic obesity were not statistically significant in OS. Severe post-transplant adverse events were more common in the low SAT group (odds ratio [OR] 3.12, 95% CI 1.32-7.40, p = 0.01) and OR 3.17, 95% CI 1.31-7.70, p =< 0.01 in the age- and sex-adjusted analysis. CONCLUSION: Low SAT and myosteatosis may contribute to an increased risk of post-transplant mortality, while low SAT appears to increase the risk of severe post-transplant adverse events.
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Composición Corporal , Trasplante de Células Madre Hematopoyéticas , Grasa Subcutánea , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Pronóstico , Sarcopenia , Anciano , Trasplante Homólogo , Músculo Esquelético , Grasa Intraabdominal , Adulto JovenRESUMEN
Studies regarding the influence of body composition parameters as predictors on overall survival (OS) in patients with multiple myeloma (MM) are scarce. OS and progression-free survival (PFS) were retrospectively assessed in 129 patients with MM undergoing autologous stem cell transplantation (ASCT) after a follow-up of 2 years. A computed tomography (CT) based semi-automated assessment of body composition was performed. No statistically significant differences were noted in 2-year OS, PFS, or post-transplant adverse events in the body composition groups of subcutaneous adipose tissue (SAT) (low vs. high-SAT), visceral adipose tissue (VAT) (low vs. high-VAT), visceral-to-subcutaneous fat ratio (VSR) (low vs. high VSR), and sarcopenia in terms of skeletal muscle index (SMI) (non-sarcopenic vs. sarcopenic). In conclusion, adipose and muscle tissue do not limit OS or affect the PFS in patients with MM undergoing ASCT.
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Composición Corporal , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Trasplante Autólogo , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Retrospectivos , Pronóstico , Adulto , Sarcopenia/etiología , Sarcopenia/diagnóstico , Estudios de Seguimiento , Tomografía Computarizada por Rayos X , Grasa Intraabdominal/diagnóstico por imagen , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Femenino , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Persona de Mediana Edad , Mieloma Múltiple/patologíaRESUMEN
BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www. CLINICALTRIALS: gov as NCT03676504.
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Síndromes de Neurotoxicidad , Humanos , Adulto , Leucaféresis , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19/uso terapéuticoRESUMEN
Low skeletal muscle mass as a proxy parameter for sarcopenia acts as a non-invasive imaging marker that is associated with poor prognosis in numerous types of cancer. The present study aimed to assess the influence of body composition parameters on overall survival (OS) and progression free survival (PFS) in patients diagnosed with primary central nervous system lymphoma (PCNSL). A total of 98 patients with PCNSL treated at University Hospital Magdeburg (Magdeburg, Germany) from 2013-2019 were retrospectively studied. Patients with a pre-treatment staging computed tomography (CT) scan that included the third lumbar vertebra were reviewed for analysis. Skeletal muscle area (SMA), skeletal muscle index (SMI), mean muscle density and skeletal muscle gauge (SMG) were measured on the CT scan prior to treatment. Parameters were associated with OS and PFS. Overall, 72 patients were included in the present study. Results of the present study demonstrated that the median OS was 10 months (range, 1-181 months), and 37 patients (51.4%) presented with sarcopenia. Moreover, the median OS was 7 months in the sarcopenic group and 32 months in the non-sarcopenic group. Results of the present study further illustrated that SMI, SMA, density and SMG did not exert a significant effect on OS. Notably, the median PFS was 2.5 months in the low SMI group and 10 months in the normal SMI group. Body composition parameters did not exert a significant effect on PFS. Overall, the results of the present study demonstrated that sarcopenia was not a risk factor for decreased OS or PFS in patients with PCNSL undergoing systemic treatment.
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BACKGROUND/AIM: Body composition assessment has shown promising results as a prognostic biomarker as depicted by cross-sectional imaging of several tumor entities including lymphomas. The present study sought to elucidate the prognostic relevance of subcutaneous and visceral fat tissue (SAT and VAT) in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: Overall, 74 patients (36 female patients, 46.7%) with a mean age of 64.2±12.8 years (range=23-81 years) were identified in the database with sufficient clinical and imaging data and included into this retrospective study. Fat area assessment was performed on one axial slide on L3-height derived from staging computed tomography (CT) images. Subcutaneous, visceral, and intramuscular adipose tissues (SAT, VAT, IMAT) were estimated. Also, density of SAT, VAT, and IMAT were estimated. Finally, the ratio VAT/SAT (VSR) was calculated. Overall and progression-free survival (OS and PFS) were used as study end points. RESULTS: In the observation period, overall, 47 patients (63.5%) died. Mean OS was 33.8±45.4 months and mean PFS was 26.6±42.7 months. The mean VAT value was 162±99.5 cm2, the mean SAT was 202.4±103.3 cm2, the mean VSR was 0.92±0.69. The hazard ratios (HRs) for overall survival were 0.87 for high VAT, 1.52 for SAT, and 0.73 for VSR in univariable analysis. For PFS it was 0.24 for VAT, 1.11 for SAT, and 1.07 for VSR. No values achieved statistical significance. Similar results were shown in Kaplan-Meier analysis for OS and PFS, respectively. CONCLUSION: Parameters of adipose tissue are not associated with OS and PFS in patients with PCNSL.
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Tejido Adiposo , Grasa Intraabdominal , Humanos , Femenino , Persona de Mediana Edad , Anciano , Pronóstico , Estudios Retrospectivos , Tejido Adiposo/diagnóstico por imagen , Grasa Intraabdominal/diagnóstico por imagen , Grasa Intraabdominal/patología , Grasa Subcutánea/diagnóstico por imagen , Sistema Nervioso CentralAsunto(s)
Leucemia de Células Plasmáticas/complicaciones , Dolor de la Región Lumbar/etiología , Humanos , Leucemia de Células Plasmáticas/sangre , Leucemia de Células Plasmáticas/diagnóstico , Leucocitosis/sangre , Leucocitosis/diagnóstico , Leucocitosis/etiología , Dolor de la Región Lumbar/sangre , Dolor de la Región Lumbar/diagnóstico , Masculino , Persona de Mediana EdadAsunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas de Neoplasias/genética , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Pirazoles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/inmunología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Antineoplásicos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Proliferación Celular/efectos de los fármacos , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Activación de Linfocitos/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/inmunología , Mutación , Proteínas de Neoplasias/inmunología , Nitrilos , Fitohemaglutininas/farmacología , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/inmunología , Policitemia Vera/patología , Cultivo Primario de Células , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/inmunología , Mielofibrosis Primaria/patología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas , Transducción de Señal , Resultado del TratamientoRESUMEN
BACKGROUND: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. RESULTS: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). CONCLUSIONS: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.
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The sonidegib and ruxolitinib combination was assessed in an open-label study in JAK inhibitor-naive patients with myelofibrosis (MF). The primary objective of phase 1b was to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and phase 2 was to assess spleen volume reduction at weeks 24 and 48. Fifty patients were enrolled. In the dose-escalation phase (n = 23), doses for sonidegib once daily/ruxolitinib twice daily were 400/10 mg (level 1, n = 8), 400/15 mg (level 2, n = 10), and 400/20 mg (level 3, n = 5). Two patients had dose-limiting toxicity at level 2: increased blood creatine phosphokinase (grades 3 and 4, n = 1 each). MTD/RP2D was determined as sonidegib 400 mg daily + ruxolitinib 20 mg twice daily. In phase 1b expansion and phase 2 stage 1 (n = 27), by weeks 24 and 48, ≥35% reduction in spleen volume was observed in 44.4% and 29.6% patients, respectively. By weeks 24 and 48, 42.0% and 26.0% patients had ≥50% reduction in Myelofibrosis Symptom Assessment Form total symptom score, respectively. Most common treatment-related adverse events (grade 3/4) were increased blood creatine phosphokinase (18%), anemia (14%), and thrombocytopenia (12%). Four deaths were reported due to multiple organ dysfunction syndrome (on-treatment; no relationship with study treatment), acute myeloid leukemia, MF progression, and aspiration pneumonia. Although well tolerated, this combination will not be further developed in MF patients due to modest overall benefit compared with historical ruxolitinib monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01787552.
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Mielofibrosis Primaria , Compuestos de Bifenilo , Humanos , Nitrilos , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/efectos adversos , Piridinas , PirimidinasRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Benzotiazoles/farmacología , Compuestos de Fenilurea/farmacología , Estaurosporina/análogos & derivados , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Humanos , Estaurosporina/farmacología , Linfocitos T/metabolismoRESUMEN
Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgl1 leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.
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Proteínas de Drosophila/fisiología , Células Madre Hematopoyéticas/fisiología , Proteínas de la Membrana/fisiología , Animales , Movimiento Celular , Proliferación Celular , Autorrenovación de las Células , Proteínas del Citoesqueleto/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Proteínas de la Membrana/metabolismo , Estrés Fisiológico , Transcripción GenéticaRESUMEN
JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, ß1 and ß2, may contribute to CMN pathophysiology remained unclear. ß1 (α4ß1; VLA-4) and ß2 (αLß2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of ß1 and ß2 integrins for their respective ligands. For ß1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-ß2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-ß2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.
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Antígenos CD18/metabolismo , Integrina beta1/metabolismo , Janus Quinasa 2/metabolismo , Mutación Missense , Trombosis de la Vena/metabolismo , Sustitución de Aminoácidos , Animales , Antígenos CD18/genética , Adhesión Celular , Integrina alfa4beta1/genética , Integrina alfa4beta1/metabolismo , Integrina beta1/genética , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Janus Quinasa 2/genética , Leucocitos/metabolismo , Leucocitos/patología , Antígeno-1 Asociado a Función de Linfocito/genética , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ratones , Ratones Mutantes , Bazo/metabolismo , Bazo/patología , Trombosis de la Vena/genética , Trombosis de la Vena/patología , Proteínas de Unión al GTP rap1/genética , Proteínas de Unión al GTP rap1/metabolismoRESUMEN
Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death.Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort.Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy.Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." Clin Cancer Res; 23(16); 4805-16. ©2017 AACR.