"Delineating aggressiveness of acute myeloid leukemia in a mouse model carrying mutations of Spi1 (PU.1) and Trp53"@en . "Studium mechanism\u016F agresivity akutn\u00ED myeloidn\u00ED leukemie v my\u0161\u00EDm modelu nesouc\u00EDm mutace gen\u016F Spi1 (PU.1) a Trp53" . . . . . "I, P(ED1.1.00/02.0109), P(GAP305/12/1033), S" . . "Studium mechanism\u016F agresivity akutn\u00ED myeloidn\u00ED leukemie v my\u0161\u00EDm modelu nesouc\u00EDm mutace gen\u016F Spi1 (PU.1) a Trp53"@cs . "Studium mechanism\u016F agresivity akutn\u00ED myeloidn\u00ED leukemie v my\u0161\u00EDm modelu nesouc\u00EDm mutace gen\u016F Spi1 (PU.1) a Trp53"@cs . "Studium mechanism\u016F agresivity akutn\u00ED myeloidn\u00ED leukemie v my\u0161\u00EDm modelu nesouc\u00EDm mutace gen\u016F Spi1 (PU.1) a Trp53" . "1"^^ . . . "11110" . . "PU.1 downregulation within haematopoietic stem and progenitor cells (HSPCs) is the primary mechanism for the development of acute myeloid leukaemia (AML) in mice with homozygous deletion of the upstream regulatory element (URE) of PU.1 gene. p53 is a well known tumor suppressor that is often mutated in human haematologic malignancies including AML and adds to their aggressiveness; however its genetic deletion does not cause AML in mouse. Deletion of p53 in the PU.1ure/ure mice (PU.1ure/urep53-/-) results in more aggressive AML with shortened overall survival. PU.1ure/urep53-/- progenitors express significantly lower PU.1 levels. In addition to URE deletion we searched for other mechanisms that in absence of p53 contribute to decreased PU.1 levels in PU.1ure/urep53-/-mice. We found involvement of Myb and miR- 155 in downregulation of PU.1 in aggressive murine AML. Upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukaemic cell growth similarly to PU.1 rescue. The MYB/miR-155/PU.1 axis is a target of p53 and is activated early after p53 loss as indicated by transient p53 knockdown. Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in pathogenesis of AML and its aggressiveness characterized by p53 mutation."@en . "Delineating aggressiveness of acute myeloid leukemia in a mouse model carrying mutations of Spi1 (PU.1) and Trp53"@en . . . . . "1"^^ . . . "Ba\u0161ov\u00E1, Petra" . . "RIV/00216208:11110/14:10283590!RIV15-MSM-11110___" . "Dizerta\u010Dn\u00ED pr\u00E1ce, UK v Praze, 190 s. Sn\u00ED\u017Een\u00ED hladiny PU.1 v hematopoetick\u00FDch kmenov\u00FDch a progenitorov\u00FDch bu\u0148k\u00E1ch (HSPCs) je prim\u00E1rn\u00EDm mechanismem pro rozvoj akutn\u00ED myeloidn\u00ED leuk\u00E9mie (AML) u my\u0161\u00ED s homozygotn\u00ED delec\u00ED %22upstream regulatory element%22 (URE) genu PU.1. p53 je tumor supresorov\u00FD gen, kter\u00FD je \u010Dasto mutovan\u00FD u lidsk\u00FDch hematologick\u00FDch malignit (v\u010Detn\u011B AML) a p\u0159isp\u00EDv\u00E1 k jejich agresivit\u011B; navzdory tomu jeho genetick\u00E1 delece nezp\u016Fsobuje u my\u0161\u00ED AML. Delece p53 u my\u0161\u00ED PU.1ure/ure (PU.1ure/urep53-/-) zp\u016Fsobuje agresivn\u00ED formu AML se zkr\u00E1cenou dobou celkov\u00E9ho p\u0159e\u017Eit\u00ED. PU.1ure/urep53-/- progenitory exprimuj\u00ED signifikantn\u011B ni\u017E\u0161\u00ED hladinu PU.1. Zam\u011B\u0159ili jsme se proto na mechanismy, je\u017E za nep\u0159\u00EDtomnosti p53 p\u0159isp\u00EDvaj\u00ED ke sni\u017Eov\u00E1n\u00ED hladiny PU.1 v PU.1ure/urep53-/- progenitorech. Nalezli jsme vliv onkogen\u016F: Myb a jeho c\u00EDle mikroRNA miR-155 na downregulaci PU.1 u agresivn\u00ED my\u0161\u00ED AML. Inhibic\u00ED onkogen\u016F Myb nebo miR-155 in vitro doch\u00E1z\u00ED u AML progenitor\u016F k znovuobnoven\u00ED hladin PU.1 a ztr\u00E1t\u011B leukemick\u00E9ho bun\u011B\u010Dn\u00E9ho r\u016Fstu podobn\u011B jako p\u0159i obnov\u011B exprese PU.1. Transientn\u00ED potla\u010Den\u00ED exprese p53 uk\u00E1zalo, \u017Ee dr\u00E1ha MYB/miR-155/PU.1 je c\u00EDlem p53, kter\u00E1 se aktivuje brzy po ztr\u00E1t\u011B p53. Deregulace MYB a miR-155 spojen\u00E1 s poklesem hladiny PU.1 byla tak\u00E9 pozorov\u00E1n\u00E1 v lidsk\u00E9 AML, co\u017E nazna\u010Duje, \u017Ee nov\u011B objeven\u00E1 onkogenn\u00ED dr\u00E1ha p53/MYB/miR-155/PU.1 m\u016F\u017Ee b\u00FDt zapojena do patogeneze lidsk\u00E9 agresivn\u00ED AML charakterizov\u00E1n\u00E9 mutac\u00ED p53." . "[09E55890A053]" . . . . . "Trp53; Spi1 (PU.1); mutations; mouse model; acute myeloid leukemia"@en . "Dizerta\u010Dn\u00ED pr\u00E1ce, UK v Praze, 190 s. Sn\u00ED\u017Een\u00ED hladiny PU.1 v hematopoetick\u00FDch kmenov\u00FDch a progenitorov\u00FDch bu\u0148k\u00E1ch (HSPCs) je prim\u00E1rn\u00EDm mechanismem pro rozvoj akutn\u00ED myeloidn\u00ED leuk\u00E9mie (AML) u my\u0161\u00ED s homozygotn\u00ED delec\u00ED %22upstream regulatory element%22 (URE) genu PU.1. p53 je tumor supresorov\u00FD gen, kter\u00FD je \u010Dasto mutovan\u00FD u lidsk\u00FDch hematologick\u00FDch malignit (v\u010Detn\u011B AML) a p\u0159isp\u00EDv\u00E1 k jejich agresivit\u011B; navzdory tomu jeho genetick\u00E1 delece nezp\u016Fsobuje u my\u0161\u00ED AML. Delece p53 u my\u0161\u00ED PU.1ure/ure (PU.1ure/urep53-/-) zp\u016Fsobuje agresivn\u00ED formu AML se zkr\u00E1cenou dobou celkov\u00E9ho p\u0159e\u017Eit\u00ED. PU.1ure/urep53-/- progenitory exprimuj\u00ED signifikantn\u011B ni\u017E\u0161\u00ED hladinu PU.1. Zam\u011B\u0159ili jsme se proto na mechanismy, je\u017E za nep\u0159\u00EDtomnosti p53 p\u0159isp\u00EDvaj\u00ED ke sni\u017Eov\u00E1n\u00ED hladiny PU.1 v PU.1ure/urep53-/- progenitorech. Nalezli jsme vliv onkogen\u016F: Myb a jeho c\u00EDle mikroRNA miR-155 na downregulaci PU.1 u agresivn\u00ED my\u0161\u00ED AML. Inhibic\u00ED onkogen\u016F Myb nebo miR-155 in vitro doch\u00E1z\u00ED u AML progenitor\u016F k znovuobnoven\u00ED hladin PU.1 a ztr\u00E1t\u011B leukemick\u00E9ho bun\u011B\u010Dn\u00E9ho r\u016Fstu podobn\u011B jako p\u0159i obnov\u011B exprese PU.1. Transientn\u00ED potla\u010Den\u00ED exprese p53 uk\u00E1zalo, \u017Ee dr\u00E1ha MYB/miR-155/PU.1 je c\u00EDlem p53, kter\u00E1 se aktivuje brzy po ztr\u00E1t\u011B p53. Deregulace MYB a miR-155 spojen\u00E1 s poklesem hladiny PU.1 byla tak\u00E9 pozorov\u00E1n\u00E1 v lidsk\u00E9 AML, co\u017E nazna\u010Duje, \u017Ee nov\u011B objeven\u00E1 onkogenn\u00ED dr\u00E1ha p53/MYB/miR-155/PU.1 m\u016F\u017Ee b\u00FDt zapojena do patogeneze lidsk\u00E9 agresivn\u00ED AML charakterizov\u00E1n\u00E9 mutac\u00ED p53."@cs . "RIV/00216208:11110/14:10283590" . . "48187" .