16 research outputs found
Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) in infants is characterized by
rearrangements of the mixed lineage leukemia (MLL) gene, drug resistance,
and a poor treatment outcome. Therefore, novel therapeutic strategies are
needed to improve prognosis. Recently, we showed that FLT3 is highly
expressed in MLL rearranged ALL (MLL). Here we demonstrate FLT3 expression
in infants with MLL (n = 41) to be significantly higher compared to both
infant (n = 8; P < .001) and noninfant patients with ALL (n = 23; P =
.001) carrying germline MLL genes. Furthermore, leukemic cells from
infants with MLL were significantly more sensitive to the Fms-like
tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than
noninfant ALL cells, and at least as sensitive as internal tandem
duplication-positive (ITD+) AML cells. Surprisingly, activation loop
mutations only occurred in about 3% (1 of 36) of the cases and no
FLT3/ITDs were observed. However, measuring FLT3 phosphorylation in
infants with MLL expressing varying levels of wild-type FLT3 revealed that
high-level FLT3 expression is associated with ligand-independent FLT3
activation. This suggests that infant MLL cells displaying activated FLT3
as a result of overexpression can be targeted by FLT3 inhibitors such as
PKC412. However, at concentrations of PKC412 minimall
The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice
More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease
Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia
MLL-rearranged acute lymphoblastic leukemia (ALL) represents an unfavorable type of leukemia that often is highly resistant to glucocorticoids such as prednisone and dexamethasone. Because response to prednisone largely determines clinical outcome of pediatric patients with ALL, overcoming resistance to this drug may be an important step toward improving prognosis. Here, we show how gene expression profiling identifies high-level MCL-1 expression to be associated with prednisolone resistance in MLL-rearranged infant ALL, as well as in more favorable types of childhood ALL. To validate this observation, we determined MCL-1 expression with quantitative reverse transcription-polymerase chain reaction in a cohort of MLL-rearranged infant ALL and pediatric noninfant ALL samples and confirmed that high-level MCL-1 expression is associated with prednisolone resistance in vitro. In addition, MCL-1 expression appeared to be significantly higher in MLL-rearranged infant patients who showed a poor response to prednisone in vivo compared with prednisone good responders. Finally, down-regulation of MCL-1 in prednisolone-resistant MLL-rearranged leukemia cells by RNA interference, to some extent, led to prednisolone sensitization. Collectively, our findings suggest a potential role for MCL-1 in glucocorticoid resistance in MLL-rearranged infant ALL, but at the same time strongly imply that high-level MCL-1 expression is not the sole mechanism providing resistance to these drugs