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  • 1
    In: HemaSphere, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. S3 ( 2023-08), p. e53119c1-
    Type of Medium: Online Resource
    ISSN: 2572-9241
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 2
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 7, No. 8 ( 2021-02-19)
    Abstract: The extensive drug resistance requires rational approaches to design personalized combinatorial treatments that exploit patient-specific therapeutic vulnerabilities to selectively target disease-driving cell subpopulations. To solve the combinatorial explosion challenge, we implemented an effective machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory acute myeloid leukemia (AML) patient cases, each with a different genetic background, we accurately predicted patient-specific combinations that not only resulted in synergistic cancer cell co-inhibition but also were capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Our functional precision oncology approach provides an unbiased means for systematic identification of personalized combinatorial regimens that selectively co-inhibit leukemic cells while avoiding inhibition of nonmalignant cells, thereby increasing their likelihood for clinical translation.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
    detail.hit.zdb_id: 2810933-8
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5067-5067
    Abstract: Despite significant advances in characterizing the molecular genetics of AML, the clonal evolution of leukemic cells and the dynamic impact of genomic changes on the development of the disease and progression to drug resistance are not well understood. Here, we applied next-generation sequencing to quantify aberrant tumor subclones carrying specific mutant alleles of key cancer genes and developed a method to extract quantitative high-resolution copy number changes across the genome using exome sequencing data from matching cancer and normal DNA. Serial bone marrow (BM) samples collected from diagnosis to relapse to post-treatment drug resistance in a patient-centric manner made it possible to trace the clonal evolution of AML and to identify variants potentially involved in drug resistance. Exome sequencing from AML blast cells and normal skin biopsies was performed as part of the Finnish Hematology Registry and Biobanking (FHRB) effort. Consecutive paired samples from different patients revealed unique genetic patterns of clonal evolution and cancer progression in each patient. In a pre-resistant sample of one AML M5 patient, we identified four closely spaced insertions in the Wilm's Tumor (WT1) suppressor gene, none of which appear on the same sequence reads. This suggests the presence of multiple distinct leukemic subclones even before treatment resistance and underscores the strong selective advantage conferred by WT1 mutations. After relapse, one of the subclones was lost, and another one significantly increased suggesting that the relapse arose from the expansion of a pre-existing resistant subclone. In this patient, recurrent clones otherwise featured similar copy number changes and the same fusion genes as the primary diagnostic sample. In another AML patient developing recurrence an opposite pattern was observed: The relapsed, drug-resistant cells displayed an enormous increase of small microdeletions compared to the diagnostic, pre-treatment sample, while almost all sequence-level alterations in potential cancer genes were the same between the two samples. This suggests that a distinct type of DNA repair deficiency may have contributed to the drug resistant clone in this patient. Conclusions: Exome sequencing from paired samples of AML cells before and after relapse makes it possible to trace the clonal evolution of the disease and study the impact of therapy both at the level of sequence alterations of key cancer genes and simultaneously at the level of copy number changes inferred from exome sequence data. This analysis has highlighted multiple genomic patterns by which resistance may evolve in vivo during cancer treatment. Refined bioinformatic analysis and interpretation of exome-seq data provides a rich resource to identify genetic biomarkers of drug response and minimal residual disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5067. doi:1538-7445.AM2012-5067
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 676-676
    Abstract: The T315I gatekeeper mutation confers resistance to majority of approved ABL1 inhibitors, with only ponatinib demonstrating efficacy in BCR-ABL1(T315I)-driven disease. However, vascular adverse events and selection of resistant compound mutations limit its clinical utility. Hence, there is an unmet need for novel therapies for patients with gatekeeper-mutated Ph+ leukemia. In this study we integrated comprehensive drug sensitivity testing with structural analysis to characterize the tyrosine kinase inhibitor axitinib as a putative novel therapy for BCR-ABL1(T315I)-driven leukemias. To address this we profiled BCR-ABL1(T315I)-driven CML/Ph+ ALL patient samples against 300 anti-cancer compounds (approved and investigational drugs). Ex vivo drug sensitivity testing of primary cells derived from a Ph+ ALL patient revealed a marked and cancer-selective response to the VEGFR inhibitor axitinib. Strikingly, axitinib exhibited higher sensitivity in T315I positive Ph+ patient samples in comparison to T315I negative CML and ALL patient samples. In line with the ex vivo drug response data, axitinib inhibited the kinase activity of ABL1(T315I) with similar potency as its primary target VEGFR2, while the potency to non-mutated ABL1 was 30-fold lower. Analogously, in engineered Ba/F3 cells, axitinib showed a 10-fold higher inhibition of T315I than non-mutated ABL1-driven autophosphorylation and cell growth. To better understand the molecular mechanisms of the BCR-ABL1(T315I) selectivity, we solved the crystal structure of axitinib in complex with ABL1(T315). The structure revealed that axitinib bound to a mutation induced active conformation of ABL1(T315I), different than the binding mode in non-mutated ABL1, likely explaining the increased potency towards ABL1(T315I). Moreover, axitinib occupied a distinct binding space than all approved ABL1 inhibitors, signifying that axitinib will have a unique mutation vulnerability profile. Compassionate two week treatment of a CML patient harboring the T315I mutation with axitinib, resulted in a 5-fold reduction of T315I transcript levels in the bone marrow, further suggesting that axitinib can produce specific and effective responses in patients with BCR-ABL1(T315I)-driven leukemia. In conclusion, we demonstrate that axitinib potently inhibits BCR-ABL1(T315I) via a gatekeeper mutant-selective mechanism. Since axitinib is in clinical use for treatment of refractory renal cell carcinoma with a manageable safety profile, our data provide a sound basis for readily repurposing axitinib for BCR-ABL1(T315I)-driven leukemia. Finally, the distinct mechanism of inhibition by axitinib serves as an exemplar for development of even more effective gatekeeper-mutant selective inhibitors targeting ABL1 as well as other clinically important kinases, such as EGFR and KIT. Citation Format: Tea Pemovska, Eric Johnson, Mika Kontro, Gretchen A. Repasky, Jeffrey Chen, Peter Wells, Ciarán N. Cronin, Michele McTigue, Olli Kallioniemi, Kimmo Porkka, Brion W. Murray, Krister Wennerberg. Axitinib targets gatekeeper-mutant BCR-ABL1(T315I)-driven leukemia in a distinct and selective fashion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 676. doi:10.1158/1538-7445.AM2015-676
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 424-424
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 424-424
    Abstract: Introduction: Most patients with acute myeloid leukemia (AML) initially respond to cytarabine-anthracycline induction chemotherapy. However, in many patients, the disease recurs in a lethal drug-resistant form. Somatic mutations underlying the pathogenesis of AML have been extensively characterized by sequencing of newly diagnosed AMLs. However, the mutations driving therapy resistance and disease progression at relapse have not been well characterized. In this study, we have exome sequenced a cohort of relapsed and refractory AMLs and compared the landscape of somatic mutations at relapse to diagnosis phase AMLs to identify mutations that contribute to therapy resistance and disease progression. Materials and Methods: We performed exome sequencing of diagnosis phase AMLs (n=70) and relapsed or primary refractory AMLs (n=54). Patients with AML M3 subtype were excluded from the study. Paired diagnosis and relapse samples were available from 27 patients. A skin biopsy was used as the germline control. Nine patients had received an allogeneic hematopoietic stem cell transplant before relapse. Somatic mutations were called using varscan2 and copy number aberrations using copyCat. Since the identification of large insertions from next-generation sequencing data remains challenging using existing algorithms, FLT3 internal tandem duplications (FLT3-ITDs) were identified using a novel custom algorithm optimized for FLT3-ITD detection. Population variants were filtered out to remove donor-derived germline variants in chimeric post-transplant relapse samples. Results: Comparison of somatic mutation frequencies in diagnosis and relapse and refractory samples showed that on average relapsed tumors have a higher number of driver mutations than tumors at diagnosis. WT1, TP53, CBL, IDH1 and PTPN11 were mutated at a higher frequency in relapsed samples than at diagnosis, with 13 %, 11 %, 11 %, 9 % and 9 % of relapsed or refractory samples and 4 %, 6 %, 3 %, 4 % and 7 % of diagnosis mutated respectively. Analysis of paired diagnosis-relapse samples showed that in patients with WT1, CBL or PTPN11 mutation at diagnosis the second allele is frequently mutated or lost due to uniparental disomy occurring at relapse. Conclusions: On average relapsed AMLs have a higher number of driver mutations than diagnosis phase AMLs indicating that acquisition of additional driver mutations contributes to relapse. AMLs frequently acquire additional mutations in the same genes and pathways that already harbored mutations at diagnosis. Citation Format: Samuli Eldfors, Mika Kontro, Yevhen Akimov, Olli Kallioniemi, Kimmo Porkka, Caroline Heckman. Landscape of somatic mutations in drug-resistant acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 424. doi:10.1158/1538-7445.AM2017-424
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 286-286
    Abstract: Acute myeloid leukemia (AML) is an aggressive, heterogeneous disease with poor survival after disease recurrence. Although new targeted therapies have recently been approved for specific AML subtypes, the majority is treated with conventional cytotoxic therapy with variable outcome. To identify novel therapies, we performed comprehensive ex vivo drug sensitivity testing with 515 drugs and RNA sequencing on 127 AML patient samples, allowing us to identify associations between transcriptomic profiles and drug responses. Bone marrow or peripheral blood mononuclear cells (MNCs) were collected from diagnostic (n=66), relapsed (n=39) and refractory (n=22) AML patients. RNA was prepared, sequenced and analyzed as described previously (PMID:28818039). Drug sensitivity and resistance testing was performed on the MNCs with 515 approved and investigational oncology chemical compounds (PMID:24056683). To identify expression profiles associated with drug response, generalized linear regression and elastic net regression models were applied. In the analysis, confounding factors including the patient's gender, RNA extraction and library preparation methods were taken into account. Elastic net regression analysis resulted in significant (FDR & lt;0.1) positive or negative associations between 1110 genes and 105 drugs. Clustering of the genes depicted 4 major hubs where drugs with the same mode of action grouped together, e.g. chemotherapeutics, BCL-2, and FLT3 inhibitors. Functional enrichment analysis of each hub using DAVID tool revealed genes involved in regulation of cell proliferation (43 genes, FDR=9.19E-18), which can be explained by the cytotoxic chemotherapy drugs. Genes involved in cell death (68 genes, FDR=1.67E-5) were associated with BCL-2 inhibitor response, while genes involved in cell surface receptor linked signal transduction (51 genes, FDR=2.33E-11) were associated with FLT3 inhibitors. The fourth hub was enriched with cell adhesion (45 genes, FDR=1.11E-21) and focal adhesion (50 genes, FDR=5.11E-28), specifically integrin family (29 genes, FDR=3.17E-18) genes, that play an important role in drug resistance and were negatively correlated with cytotoxic drugs. Finally, the linear regression analysis revealed significant positive correlation between tyrosine kinase inhibitors (sorafeninb, sunitinib, tivozanib) and FLT3LG and KITLG and negative correlation with BEX2 and BEX5 genes. Regression analysis for MEK inhibitors resulted in expected positive correlation with RRAS and JAK2 gene expression. In conclusion, identifying associations between transcriptomic profiles and drug responses may reveal clinically actionable drugs for AML patients characterized by specific molecular features. Our results indicate potential gene expression biomarkers for key targeted drugs, which can be used to identify AML patients likely to benefit from these therapies. Citation Format: Ashwini Kumar, Disha Malani, Bhagwan Yadav, Mika Kontro, Matti Kankainen, Swapnil Potdar, Simon Anders, Kimmo Porkka, Olli Kallioniemi Kallioniemi, Caroline Heckman. Transcriptomic features predicting drug sensitivity and resistance in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 286.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 410466-3
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  • 7
    In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 10 ( 2020-10), p. 2780-2784
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2008023-2
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  • 8
    In: Cellular and Molecular Life Sciences, Springer Science and Business Media LLC, Vol. 78, No. 23 ( 2021-12), p. 7851-7872
    Abstract: Although the development of hematopoietic stem cells (HSC) has been studied in great detail, their heterogeneity and relationships to different cell lineages remain incompletely understood. Moreover, the role of Vascular Adhesion Protein-1 in bone marrow hematopoiesis has remained unknown. Here we show that VAP-1, an adhesin and a primary amine oxidase producing hydrogen peroxide, is expressed on a subset of human HSC and bone marrow vasculature forming a hematogenic niche. Bulk and single-cell RNAseq analyses reveal that VAP-1 + HSC represent a transcriptionally unique small subset of differentiated and proliferating HSC, while VAP-1 − HSC are the most primitive HSC. VAP-1 generated hydrogen peroxide acts via the p53 signaling pathway to regulate HSC proliferation. HSC expansion and differentiation into colony-forming units are enhanced by inhibition of VAP-1. Contribution of VAP-1 to HSC proliferation was confirmed with mice deficient of VAP-1, mice expressing mutated VAP-1 and using an enzyme inhibitor. In conclusion, VAP-1 expression allows the characterization and prospective isolation of a new subset of human HSC. Since VAP-1 serves as a check point-like inhibitor in HSC differentiation, the use of VAP-1 inhibitors enables the expansion of HSC.
    Type of Medium: Online Resource
    ISSN: 1420-682X , 1420-9071
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1458497-9
    SSG: 12
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  • 9
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4029-4029
    Abstract: Introduction T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy affecting 10-15% of pediatric ALL patients. Current cure rates of pediatric patients is 80% but increasing understanding of the molecular mechanisms of T-ALL provides possibilities for more effective and targeted therapies. During the last decade targeted therapies with tyrosine kinase inhibitors (TKI) have proven to be effective in BCR-ABL1 fusion positive leukemias. Several studies have suggested TKI dasatinib to be effective also in the treatment of NUP214-ABL1 positive T-ALLs, which comprise approximately 4-10% of the T-ALL cases. Materials and Methods In silico drug screening was performed by comparing gene expression profiles of 4769 leukemic samples to a library of 13384 compounds and their known targets from the Drug signature database (DsigDB). These compounds included FDA approved therapeutic molecules and molecules under studies. Findings were validated in an ex vivo drug screen, consisting of 20 T-ALL bone marrow samples and 9 healthy bone marrow controls. Samples were treated for 72 hours with five different concentrations of dasatinib in 10-fold dilutions (0.1-1000nM), cell viability was measured and the data normalized to negative (DMSO) and positive (benzethonium chloride) controls. The effect of dasatinib was further explored in vitro by treating one NUP214-ABL1 fusion positive and six fusion negative T-ALL cell lines with dasatinib (1-1000nM). Gene expression levels of the known dasatinib targets in these cell lines were measured by Global Run On sequencing (GRO-seq) assay and qRT-PCR. Results In order to find novel targeted therapies for T-ALL, we performed an in silico drug target screen. A dasatinib-targetable gene LCK was strongly expressed in a number of T-ALL cases whereas normal T-lymphoid cells had lower expression. Chemical screen data of the target specificity of dasatinib showed high inhibition of LCK with percent of control (POC) value of 1, meaning that 0.1µM concentration of dasatinib decreases the kinase activity of LCK to 1% in comparison to control. In vitro dasatinib decreased cell viability in fusion negative Jurkat and MOLT-16 cells, and also in fusion positive cell line Peer. GRO-seq and qRT-PCR confirmed the expression of LCK and several other known dasatinib targets, including other SRC family kinases, in Jurkat and MOLT-16 cell lines. However, some LCK-expressing T-ALL cell lines were less sensitive to dasatinib. In further validation, ex vivo drug testing of patient samples revealed a marked response in 6/20 patient samples with IC50 values ranging between 1.3 - 8.2nM, while in healthy bone marrow controls IC50 values were 〉 1000nM. Conclusion Our in silico drug screen identified dasatinib as a potential targeted therapy for a subgroup of T-ALL cases, and this finding was further supported by both ex vivo and in vitro studies. The exact mechanism remains to be elucidated but a number of SRC family kinases, which could potentially be targeted by dasatinib, showed expression in T-ALL samples. Disclosures Heckman: Celgene: Research Funding; Pfizer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 11751-11752
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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