RESUMEN
Chronic myeloid leukemia (CML) patients with complex chromosomal translocations as well as non-compliant CML patients often demonstrate short-lived responses and poor outcomes on the current therapeutic regimes using Imatinib and its variants. It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this Imatinib-resistant CD34(+) LSCs. Our work here identifies the molecular mechanism of Shh-mediated mutation-independent Imatinib resistance that is most relevant for treating CML-variants and non-compliant patients. Our results elucidate that while Shh can impart stemness, it also upregulates expression of anti-apoptotic protein-Bcl2. It is the upregulation of Bcl2 that is involved in conferring Imatinib resistance to the CD34(+) LSCs. Sub-toxic doses of Bcl2 inhibitor or Shh inhibitor (<Asunto(s)
Antineoplásicos/farmacología
, Cromosomas Humanos
, Resistencia a Antineoplásicos
, Proteínas Hedgehog/metabolismo
, Mesilato de Imatinib/farmacología
, Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico
, Células Madre Neoplásicas/efectos de los fármacos
, Inhibidores de Proteínas Quinasas/farmacología
, Proteínas Proto-Oncogénicas c-bcl-2/metabolismo
, Protocolos de Quimioterapia Combinada Antineoplásica/farmacología
, Resistencia a Antineoplásicos/genética
, Regulación Neoplásica de la Expresión Génica
, Proteínas Hedgehog/antagonistas & inhibidores
, Proteínas Hedgehog/genética
, Humanos
, Células K562
, Leucemia Mielógena Crónica BCR-ABL Positiva/genética
, Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo
, Leucemia Mielógena Crónica BCR-ABL Positiva/patología
, Células Madre Neoplásicas/metabolismo
, Células Madre Neoplásicas/patología
, Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores
, Proteínas Proto-Oncogénicas c-bcl-2/genética
, Tiazoles/farmacología
, Regulación hacia Arriba
, Alcaloides de Veratrum/farmacología
RESUMEN
During 2012-2013, at a public hospital in Pune, India, 26 (3.9%) cases of tuberculosis were reported among 662 medical trainees, representing an estimated incidence of 3,279 cases/100,000 person-years. Three of these infections were isoniazid-resistant, 1 was multidrug-resistant, and 1 occurred in a trainee who had fulminant hepatitis after starting treatment for TB.