RESUMEN
A 76-year-old gentleman presented with persistent lower urinary tract symptoms. Multiple biopsies, radiological correlation and ancillary studies were required to achieve a diagnosis. The main differential diagnoses lies between urothelial carcinoma and anaplastic large cell lymphoma (ALCL), both of which are known to be positive for p63 and GATA3. An accurate diagnosis is crucial as the management is significantly different. To avoid misdiagnosis a comprehensive immunohistochemistry panel is necessary. Primary bladder lymphomas are rare. Our case represents the first case of primary ALK-negative TP63-rearranged ALCL. We reviewed the literature and discussed the potential pitfalls for misdiagnosis.
Asunto(s)
Carcinoma de Células Transicionales , Linfoma Anaplásico de Células Grandes , Neoplasias de la Vejiga Urinaria , Masculino , Humanos , Anciano , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genética , Proteínas Tirosina Quinasas Receptoras/genética , Errores Diagnósticos , Factores de Transcripción/genética , Proteínas Supresoras de TumorRESUMEN
Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.
Asunto(s)
Cianoacrilatos/farmacología , Dinaminas/antagonistas & inhibidores , Endocitosis/efectos de los fármacos , Indoles/farmacología , Leucemia Mieloide/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Enfermedad Aguda , Animales , Línea Celular Tumoral , Dinaminas/metabolismo , Humanos , Leucemia Mieloide/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Células Madre Neoplásicas/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Supplemental Digital Content is available in the text.
RESUMEN
Pre-leukemic stem cells (pre-LSCs) give rise to leukemic stem cells through acquisition of additional gene mutations and are an important source of relapse following chemotherapy. We postulated that cell-cycle kinetics of pre-LSCs may be an important determinant of clonal evolution and therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia to study cell cycle in vivo, we show that self-renewal, clonal evolution and therapeutic resistance are limited to a rare population of pre-LSCs with restricted cell cycle. We show that proliferative pre-LSCs are unable to return to a cell cycle-restricted state. Cell cycle-restricted pre-LSCs have activation of p53 and its downstream cell-cycle inhibitor p21. Furthermore, absence of p21 leads to proliferation of pre-LSCs, with clonal extinction through loss of asymmetric cell division and terminal differentiation. Thus, inducing proliferation of pre-LSCs represents a promising strategy to increase cure rates for acute leukemia.