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author:("sturhan, Ali")
1.  ATM-deficiency sensitizes Mantle Cell Lymphoma cells to PARP-1 inhibitors 
Molecular cancer therapeutics  2010;9(2):347-357.
Poly-ADP ribose polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept, termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The Ataxia-Telangiectasia Mutated (ATM) gene is altered in a number of human cancers including Mantle Cell Lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition, than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (previously known as AZD2281/KU-0059436) significantly decreased tumour growth and increased overall survival in mice bearing subcutaneous xenografts of ATM-deficient Granta-519 cells, while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL and the concept of synthetic lethality extends to human cancers with ATM alterations.
doi:10.1158/1535-7163.MCT-09-0872
PMCID: PMC3729269  PMID: 20124459
ATM; Mantle Cell Lymphoma; olaparib/AZD2281; PARP-1; synthetic lethality
2.  Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1–BCR-ABL–JAK2 Complex 
Background
Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown.
Methods
The AHI-1–BCR-ABL–JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL + cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided.
Results
The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1–overexpressing and IM-resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34+ leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy.
Conclusions
Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.
doi:10.1093/jnci/djt006
PMCID: PMC3601953  PMID: 23446755
3.  The HOXB4 Homeoprotein Promotes the Ex Vivo Enrichment of Functional Human Embryonic Stem Cell-Derived NK Cells 
PLoS ONE  2012;7(6):e39514.
Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34+CD45RA+ precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells.
doi:10.1371/journal.pone.0039514
PMCID: PMC3384663  PMID: 22761810
4.  Identification of Spectral Modifications Occurring during Reprogramming of Somatic Cells 
PLoS ONE  2012;7(4):e30743.
Recent technological advances in cell reprogramming by generation of induced pluripotent stem cells (iPSC) offer major perspectives in disease modelling and future hopes for providing novel stem cells sources in regenerative medicine. However, research on iPSC still requires refining the criteria of the pluripotency stage of these cells and exploration of their equivalent functionality to human embryonic stem cells (ESC). We report here on the use of infrared microspectroscopy to follow the spectral modification of somatic cells during the reprogramming process. We show that induced pluripotent stem cells (iPSC) adopt a chemical composition leading to a spectral signature indistinguishable from that of embryonic stem cells (ESC) and entirely different from that of the original somatic cells. Similarly, this technique allows a distinction to be made between partially and fully reprogrammed cells. We conclude that infrared microspectroscopy signature is a novel methodology to evaluate induced pluripotency and can be added to the tests currently used for this purpose.
doi:10.1371/journal.pone.0030743
PMCID: PMC3326006  PMID: 22514597
5.  AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells 
The Journal of Experimental Medicine  2008;205(11):2657-2671.
Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL–transduced lin−CD34+ human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL–inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2–STAT5. Moreover, we identified an AHI-1–BCR-ABL–JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2–STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.
doi:10.1084/jem.20072316
PMCID: PMC2571939  PMID: 18936234
6.  Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects 
Journal of Clinical Investigation  2004;114(3):379-388.
Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell–dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-γ production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
doi:10.1172/JCI200421102
PMCID: PMC489961  PMID: 15286804

Results 1-6 (6)