Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia

Departments of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Blood (Impact Factor: 10.45). 12/2009; 115(9):1735-45. DOI: 10.1182/blood-2009-07-235143
Source: PubMed


To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappaB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.

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    • "Several groups have documented a functional relationship between the PI3K and Notch1 signaling pathways in T-ALL. Notch1- driven T-ALLs display increased PI3K signaling [9] that has been linked to inhibition of the p53 tumor suppressor [10]. In established T-ALL cell lines, Notch1 dependence inversely correlates with Pten expression status: pan-Notch inhibition using gammasecretase inhibitors (GSIs) impairs T-ALL growth, proliferation and glucose uptake in a manner that correlates with derepression of Pten through inhibition of expression of Hes1, a Notch1 downstream target and transcription repressor; in contrast, Pten deficiency and constitutive Akt signaling confer GSI resistance [11]. "
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    ABSTRACT: T cell acute lymphoblastic leukemias (T-ALLs) commonly display constitutively active PI3K/mTOR and Notch signaling. However, controversy surrounds whether these pathways have independent functions and whether Pten loss is sufficient to generate resistance to Notch inhibition. Here we report that Pten(-/-) T-ALL is sensitive to either PI3K/mTOR or Notch inhibition alone, each pathway controling distinct downstream signaling events that cannot be rescued by activation of the other pathway, consistent with independent, non-redundant functions. Although many human T-ALLs display constitutively activating Notch1 mutations, primary Pten(-/-) T-ALLs expressed wild-type Notch1 and depended on the Notch ligand DLL4 in vivo. Pten(-/-) T-ALLs with or without γc/TCR signaling responded similarly to PI3K/mTOR and Notch inhibition, although extended culture in vitro occasionally induced Notch-independent growth. However, unlike the T-ALLs lacking only Pten, eight of 23 Pten(-/-) T-ALLs that also lacked γc/TCR signaling accumulated Notch1 mutations, suggesting crosstalk between γc/TCR and Notch signaling. Importantly, we concluded that loss of γc/TCR signaling also inhibited thymic exit of Pten(-/-) T-ALLs. Our results may be clinically relevant in revealing that Pten loss is not sufficient to engender resistance to Notch inhibition, uncovering a role in T-ALL for ligand-dependent induction of wild-type Notch1, and suggesting that γc/TCR signaling could be targeted for preventing metastasis.
    Full-text · Article · Dec 2013 · Cancer letters
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    • "Alternatively, combination therapies of GSIs with chemotherapy or other molecularly target agents could increase the antileukemic effects of these drugs facilitating the use of decreased GSI dosing with reduced GSI-induced gut toxicity. Combination treatment of GSIs with drugs targeting NFkB signaling [Vilimas et al. 2007], CDK inhibitors [Rao et al. 2009], PI3K– AKT–mTOR inhibitors [Chan et al. 2007; Cullion et al. 2009; Palomero et al. 2007; Sanda et al. 2010], and HDAC inhibitors [Sanda et al. 2010] have been proposed. "
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    ABSTRACT: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus.
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    • "This raises the possibility that the cytotoxic effects of HSP90 inhibitors in JAK2­dependent cells involve additional pathways beyond JAK–STAT signaling. A prime candidate is AKT, which is known to be an HSP90 client and can be therapeutically targeted in a large fraction of B­ALL cases (Abramson et al., 2009; Levy et al., 2009; Sanda et al., 2010). However, AUY922 had minimal effects on total AKT in MUTZ­5 and MHH­CALL4 cells (Fig. 4). "
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    ABSTRACT: Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.
    Full-text · Article · Feb 2012 · Journal of Experimental Medicine
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