bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pro-Apoptotic Effect of Lenalidomide (L) in Patients with Chronic Lymphocytic Leukemia (CLL) Is Possibly Mediated through Interruption of the Phosphatidylinositol Pathway.
Authors: Chanan-Khan Asher Alban , Ersing Noreen , Krammer Deborah , Bernacki Ralph , Coignet Lionel , Goodrich David , Bangia Naveen , Padmanabhan Swami , Porter Carl W. 
Published: October 2019

Abstract
Introduction: In a phase II clinical trial we reported the antileukemic effect of L in CLL pts. In this clinical trial 24/34 (70.5%) pts with detectable tumor cells (ALC > 5,000) in peripheral blood demonstrated a decrease in ALC within 8 days of treatment. Although, the exact molecular mechanism for its antitumor activity remains undetermined, L has been reported to down regulates production of various cytokines including VEGF, IL-6 and TNF-alpha. In order to investigate the underlying mechanism(s) responsible for the antileukemic effects of L in CLL, we examined down stream targets of VEGF and IL-6 signaling pathways in CLL cells obtained from pts pre and post 8 day treatment with L.
Method: Pts with accessible tumor cells in blood (ALC > 5000) who received L were identified. Tumor cells were obtained prior to (baseline) and 8 days after treatment with L. Whole cell lysate was prepared and expression of down stream targets of VEGF, AKT and Erk determined through immunobloting assay.
Results: In cells obtained from pts who had received 8 days of treatment, we observed that L decreased the expression of pAKT and pErk1/2 without changes in corresponding total protein. Conversely L did not have any effect on protein expression of the Bcl-2 or Bcl-xl, though Mcl-1 was decreased compared to pretreatment control.
Conclusion: This is the first time that the antileukemic effect of L in CLL may at least be attributed to down regulation of VEGF and IL-6 mediated prosurvival pathways. Our observation that L does not interrupt the Bcl-2 pathway are clinically intriguing and propose the possibility of combining L with Bcl-2 inhibiting agent(s) to augment the antitumor response in CLL.
Jak2: A Potential Therapeutic Target for Chronic Myelogenous Leukemia (CML).
Authors: Samanta Ajoy K. , Lin Hui , Sun Tong , Kantarjian Hagop , Arlinghaus Ralph B. 
Published: October 2019

Abstract
In most CML patients Bcr-Abl, a constitutively active tyrosine kinase derived from the Philadelphia chromosome, is highly expressed and is the causative factor in most CML patients. Imatinib mesylate, an inhibitor of the Bcr-Abl kinase, is a very effective drug for treatment of CML. However in some CML patients, drug resistance develops and the patients relapse. Thus, alternative drug targets need to be identified. We have shown that Bcr-Abl activates its downstream target, the Jak2 tyrosine kinase, leading to the enhancement of c-Myc expression (Xie et al. Oncogene21: 7137, 2002; Samanta et al. Cancer Res.66: 6468, 2006). Our recent studies showed that Bcr-Abl activated the transcriptional factor NF-kB through Jak2, which in turn activated c-Myc transcription. Jak2 also activated Akt, which increased c-Myc protein levels by inhibiting GSK3. Addition of AG490, an inhibitor of the Jak2 kinase, prevented enhanced expression of c-Myc and caused induction of apoptosis in BCR-ABL+ leukemia cells. Immunoprecipitation experiments showed that Bcr-Abl is associated with a cluster of signaling proteins including Jak2, Gab2, Akt and GSK3b. Treatment of CML cell lines and mouse BCR-ABL+ 32D cells (myeloid lineage) with the either Jak2 siRNA or the Jak2 kinase inhibitor AG490 caused inhibition of pTyr Gab2 formation, pSer Akt formation and the activation of NFkB. Of interest, treatment of BCR-ABL+ 32 D cells with IL-3 reversed the apoptotic effects of imatinib by activation of Jak2 even though Bcr-Abl was inhibited. Importantly, mouse BaF3 hematopoietic cells expressing the T315I and E255K imatinib-resistant mutants of BCR-ABL underwent apoptosis upon exposure to either the Jak2 inhibitor AG490 or siRNA for Jak2, yet were resistant to imatinib. Cells from a number of CML patients (including six chronic phase, one accelerated phase, and two blast crisis patients who failed imatinib treatment) were induced to enter apoptosis upon treatment with AG490, whereas normal samples were not affected by AG490. Further analysis of imatinib resistant Bcr-Abl cell lines showed that transfection of the cells with Jak2 specific siRNA or by treating the cells with AG490 reduced levels of pLyn, pAkt, c-Myc and pGSK3 level compared to untreated cells. Transfection of Lyn specific siRNA into K562 and 32Dp210 cells resulted in down-regulation of pGab2, pAkt, pGsk3 and c-Myc, but did not alter pJak2 levels; this result indicates that pLyn is downstream of Jak2 but upstream of Gab2, pAkt, pGSK3 in BCR-ABL+ leukemia cells. We hypothesize that Jak2 activation of Lyn tyrosine kinase in BCR-ABL+ leukemia cells leads to tyrosine phosphorylation of the YxxM motif of Gab2, which activates the PI-3 kinase-Akt pathway. In conclusion, since inactivation of Jak2 inhibits many of the critical oncogenic targets of Bcr-Abl (resulting in apoptosis induction), we propose that Jak2 is a potential therapeutic target for CML, in both imatinib sensitive and imatinib resistant patients.
Bcr-Abl Regulates IRES-Dependent Translation of Lymphoid Enhancer Factor-1 in Chronic Myelogenous Leukemia.
Authors: Jimenez Judy , Zhang Min , Waterman Marian L. , Ong Tiong 
Published: October 2019

Abstract
The constitutive tyrosine kinase activity of Bcr-Abl leads to aberrant expression of multiple genes by several mechanisms, including dysregulation of transcription. Recently though, increasing attention has been focused on the effect of Bcr-Abl in dysregulating translation. Our group has previously documented the effects of Bcr-Abl on key regulators of cap-dependent translation and the role that this mechanism plays in transformation (Ly et al, Cancer Research, 2003; Prabhu et al., Oncogene, in press). Here we describe a novel form of translational control by Bcr-Abl. Specifically, we show how Bcr-Abl regulates cap-independent translation of Lymphoid Enhancer Factor-1 (LEF-1) via a bona fide internal ribosome entry site (IRES) in the 5′ untranslated region (UTR) of LEF1. Lymphoid Enhancer Factor-1 (LEF-1), a transcription factor that mediates Wnt signals via interaction with β-catenin, is often expressed in cancers derived from aberrant Wnt signaling. Lately, it has been reported that LEF1 transcripts are elevated in CML. We examined LEF-1 expression in primary CML cells and cell lines (K562 and Ba/F3-Bcr-Abl) and show that LEF-1 protein is detected in all patient-derived cells. Treatment of these cells with the Bcr-Abl imatinib mesylate (imatinib) inhibits LEF-1 expression in imatinib-sensitive cancers, but not in cancers that exhibit clinical resistance even though such cancers express imatinib-sensitive Bcr-Abl. For those cancers that are sensitive, inhibition of Bcr-Abl has a partial effect on LEF1 mRNA levels, and a significant effect on LEF-1 protein levels. LEF-1 protein is produced via two IRESs in it’s 5′ UTR. IRES-driven translation of LEF-1 was highly sensitive to Bcr-Abl as treatment with imatinib reduced IRES activity 5 fold. Transfection of CML cells with dicistronic mRNAs suggests that Bcr-Abl stimulates LEF-1 protein production through steps in the nucleus and cytoplasm. We propose that, in addition to its strong effects on cap-dependent translation in CML, Bcr-Abl is an important regulator of alternative translation pathways. mRNAs that are translated via IRES-dependent mechanisms are particularly relevant to cancer since they encode proteins that regulate cell proliferation and survival. Together, these observations underscore the important role which dysregulated translation plays in transformation, and suggest novel approaches with which to counteract the transforming properties of Bcr-Abl.
Increase in Leukemic Stem Cells Is Associated with Acceleration of BCR-ABL-Induced CML in P-Selectin-Deficient Mice.
Authors: Kong Linghong , Hu Yiguo , Peng Cong , Wang Zhu , Duffy Ted , Goodrich Ami , Li Shaoguang 
Published: October 2019

Abstract
The BCR-ABL oncogene causes chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) in human, and CML-like disease and lymphoid leukemia in mice. Recent studies show that cell adhesion molecule P-selectin is a potent negative regulator of human hematopoietic progenitors. Our previous work shows that lack of P-selectin accelerates the development of BCR-ABL-induced CML in mice (Shawn et al, Blood, 104[7]:2163-2171, 2004, PMID: 15213099). We have observed that BCR-ABL-expressing Lin-c-Kit+ Sca-1+ bone marrow (BM) cells function as leukemic stem cells (LSCs). We tested whether LSCs play a role in the acceleration of CML development. We found that the percentage of LSCs in BM of P-selectin−/− CML mice was significantly higher than those in wild type C57BL/6 (B6) CML mice; other BM populations such as CMP, GMP, and MEP had no significant differences between the two groups of CML mice, suggesting that LSCs are responsible for the acceleration of CML disease when P-selectin is deficient. We also analyzed BM of B6 and P-selectin−/− mice and the BM of B6 and P-selectin−/− mice transplanted with BM transfected with empty vector virus. We found that there was no significant difference in the percentage of the stem cell population between the two groups of mice. This suggests that the higher percentage of LSCs in P-selectin−/− CML mice is caused by BCR-ABL but not by transplantation procedure associated with the P-selectin deficiency. Taken together, our results demonstrate that in CML mice, increased LSC population in P-selectin-deficient CML mice is associated with the acceleration of CML development.
Outcomes by Cytogenetic and Molecular Response at 12 and 18 Months of Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) in the IRIS Trial.
Authors: Baccarani Michele , Guilhot Francois , Larson Richard A. , O’Brien Stephen G. , Druker Brian J. ,   on Behalf of the IRIS Study Group
Published: October 2019

Abstract
Long term data is now available from the International Randomized Study of Interferon vs. STI571 (IRIS). We performed landmark analyses for pts on imatinib (IM) at 12 and 18 months (mos) (n=509 and n=480 respectively) and stratified for CCyR (Ph+ 0%), PCyR (Ph+ >0–35%) or No MCyR (Ph+ >35%) at both timepoints. Progression-free survival (PFS) included all progressions to accelerated phase or blast crisis during treatment with IM, whereas event-free survival (EFS) also included any loss of MCyR/CHR, increase in WBC and CML-unrelated deaths on treatment as events. Overall survival (OS) considered all deaths including those after discontinuation of IM and irrespective of whether pts went on to transplant.
Outcomes in IM pts by cytogenetic response at 12 and 18 mos Estimated long-term outcomes at 60 mos (%) CcyR CcyR EFS PFS OS by 30 mos (%) by 60 mos (%) 12 mos landmark CCyR N = 350 93 97 95 – – PCyR N = 86 78 93 90 57 64 No MCyR N = 73 61 81 80 21 36 18 mos landmark CCyR N = 358 96 99 97 – – PCyR N = 66 80 90 90 38 50 No MCyR N = 56 69 83 82 11 27
Although the level of cytogenetic response was predictive for long-term outcomes, PFS and OS were not statistically significantly different between 12-mos CCyR and PCyR. Note that 64% of PCyR pts and 36% of pts without MCyR at 12 mos subsequently achieved CCyR. Using the 18-mos landmark, 50% of PCyR pts and 27% of pts without MCyR achieved CCyR at a later time. Long-term outcomes were evaluated based on available BCR-ABL transcript levels in pts with CCyR. A 3-log reduction from standardized baseline value in untreated pts was defined as a major molecular response (MMR). No pts who achieved both CCyR and MMR at 12 or 18 mos progressed to AP/BC by 60 mos. Approximately 5% of pts with CCyR but no MMR at 12 mos (p=0.007) and only 2% of CCyR pts without MMR at 18 mos (p=0.11) subsequently progressed. Of approximately 25% of CCyR pts with available PCR analysis who did not achieve MMR at 18 mos, about half did achieve MMR at a later time and their estimated EFS rate at 60 mths was 91%.
At 60 mos, 69% of patients randomized to IM remained on treatment. Achievement of CCyR and MMR by 12 and 18 mos after start of IM in newly diagnosed CML-CP are predictive for favorable long-term outcomes. About 50% of pts in PCyR or CCyR at these time points eventually achieve CCyR and MMR, respectively, on continued IM treatment. The ability to identify patients who may be late responders should be further studied.
Adaptive Autocrine Secretion of the Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Mediates Imatinib- and Nilotinib-Resistance in BCR/ABL-Positive Progenitors Via JAK-2/STAT-5 Pathway Activation.
Authors: Burchert Andreas , Wang Ying , Brendel Cornelia , Erben Philipp , Manley Paul W. , Hochhaus Andreas , Cai Dali , Neubauer Andreas 
Published: October 2019

Abstract
Overcoming disease persistence in chronic myeloid leukemia (CML) patients is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL positive cells in presence of imatinib mesylate (IM, Gleevec™) and nilotinib (AMN107, NI), a novel more selective Abl inhibitor. Conditioned media (CM) of IM-resistant LAMA84-cell clones (R-CM) was found to substantially protect IM-naïve LAMA cells and primary CML progenitors from IM- or NI-induced cell death. This was due to an increased secretion of the granulocyte-macrophage colony stimulating factor (GM-CSF) which was identified as the causative factor mediating IM resistance in R-CM. GM-CSF elicited IM and NI drug resistance via a BCR/ABL-independent activation of the JAK-2/STAT-5 signaling pathway in GM-CSF-receptor alpha receptor (CD116) expressing cells, including primary CD34+/CD116+ GM-progenitors (GMP). In a cell based resistance induction assay, GM-CSF enabled the evolution of IM- and NI-resistant colonies. When analysing GM-CSF expression in over 120 patient samples of first diagnosis CML patients and resistant patient, elevated mRNA and protein levels of GM-CSF were detected exclusively in IM-resistant patient samples, suggesting a contribution of GM-CSF secretion for IM and NI resistance in vivo. Importantly, inhibition of JAK-2 with AG490 abrogated GM-CSF-mediated STAT-5 phosphorylation and NI resistance in vitro. Together, this suggests that adaptive autocrine secretion of GM-CSF and cytokines in general may be a novel IM and NI resistance mechanism, which may also contribute to CML-persistence. GM-CSF protects CML-progenitors via a BCR/ABL-independent activation of the anti-apoptotic JAK-2/STAT-5 pathway. Inhibition of JAK-2 overcomes GM-CSF-induced IM and NI progenitor cell resistance providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML.
In CML, Marrow Fibrosis Relapses or Emerges in 5 - 6 % of Patients Per Year Independently Indicating Imatinib Failure and Shortened Survival Time of Patients.
Authors: Buesche Guntram , Hehlmann Rudiger , Ganser Arnold , Hecker Hartmut , Hochhaus Andreas , Heimpel Hermann , Heinze Barbara , Schoch Claudia , Gadzicki Dorothea , Mueller Martin , von Neuhoff Nils , Schnittger Susanne , Schlegelberger Brigitte , Frye Bernd , Georgii Axel , Kreipe Hans 
Published: October 2019

Abstract
Imatinib may reverse bone marrow fibrosis (MF) in chronic myeloid leukemia (CML). The risk of emergence or relapse of MF and its prognostic relevance are not known as yet. 110 patients with Ph+ CML recruited in two trials and treated with 400 mg imatinib / day were examined for the risk of MF and its prognostic significance.
Imatinib effectively reversed pretreatment MF (P = 0.0002), and pretreatment fiber increase did not significantly reduce the probability of achieving a hematologic, cytogenetic and major molecular response. However, during a follow-up period of 4 years, small foci with fiber increase (FFI) and MF relapsed in 13 % (5 / 38) of patients, and among patients with an initial normal fiber content (n = 72), FFI emerged in 26 % with transformation to full-blown MF in 38 % of them. FFI occurred in 3 / 27 cases with a major molecular response. The risk of emergence or relapse of FFI amounted to 13.7 % and of full-blown MF to 5.9 % per year, and the risk of acceleration and death increased to 90 % two years after occurrence of MF. FFI could be predicted neither by the risk score (Sokal, Hasford) nor the hematologic, cytogenetic and molecular response, nor by clonal evolution during imatinib treatment. In multivariate analysis, emergence or relapse of FFI and MF turned out to be a significant independent predictor of imatinib failure (P = 0.0003) as well as of acceleration and death of patients (P < 0.0009).
CONCLUSION: Although imatinib reverses initial MF in CML, it does not guarantee against relapse or emergence of MF which affects ~ 6 % of patients per year and therefore, may become a major problem during long-term therapy of CML. Focal evolution of MF should be included in the definitions of imatinib failure and accelerated phase, and continuing imatinib treatment at the current dose is no longer appropriate for patients with emergence of FFI or MF during therapy - regardless of the degree of hematologic, cytogenetic and molecular response.
Robust Anti-Leukemia CD4+ and CD8+ T Cell Responses in CML Patients Treated with Imatinib Mesylate.
Authors: Chen Christiane I.-U. , Johannsen Alexandre , Witteles Wesley , Maecker Holden T. , Lee Peter P. 
Published: October 2019

Abstract
Imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, has revolutionized the treatment of CML and is the first-line therapy for most patients. Most CML patients in chronic phase achieve hematologic remission under treatment with imatinib, with up to 70% also achieving cytogenetic remission. However, imatinib therapy is not curative, as patients who discontinue the drug invariably relapse. Thus, the need to find alternate, potentially curative therapies remains. Low levels of CD8+ T cell responses to certain HLA restricted peptides have been detected in CML patients after successful treatment. To determine, if CML patients in remission on imatinib develop and sustain anti-leukemia CD4+ or CD8+ T cell responses, blood samples from patients before and several time points after treatment were collected and analyzed. Pre-treatment samples were utilized as sources of autologous leukemic cells to detect anti-leukemia T cell responses in post-treatment remission samples. Autologous leukemic samples alone and remission samples alone served as controls. In 7 of the 14 patients investigated, significant IFN-γ responses (p<0.01) in ELISPOT assay were detectable when patients achieved cytogenetic remission, and peaked at 10–15 months (median 36 SFCs, range 26–71 SFCs), before they slowly decreased (up to 46 months post-treatment) to levels similar to those from leukemic samples alone and remission samples alone (6 SFCs, range 0–13 SFCs). These results correlated with T cell responses in cytokine flow cytometry (TNF-α 1.4–40%, IFN-γ 1.0–6.6%, p<0.05), and showed a predominance for CD4+ T cells. Furthermore, TNF-α and IFN-γ production (p<0.05) was confirmed in CD4+ and CD8+ T cell clones generated in a remission sample from one patient using multiplex cytokine assay: 6.43–37.90 pg/ml for TNF-α, 14.90–110.42 pg/ml for IFN-γ. CD8+ T cell clones (HLA-A0201+) were tested for reactivity against HLA-A0201 restricted peptides derived from leukemia associated antigens proteinase 3, Wilms tumor 1 and bcr/abl, as well as tumor associated antigens p53, p68, and human telomerase (hTERT) in IFN-γ ELISPOT assays. No IFN-γ responses were detected in the CD8+ T cell clones when stimulated with the peptides compared to stimulation with an irrelevant peptide (0–15 SFCs, p=0.55), suggesting that these clones react to as yet to be defined leukemia associated antigens. Together, these data show that CD4+ T cells play an important role in anti-leukemia immune responses in patients in remission (sustained over time) and might contribute to killing of leukemic cells, possibly via TNF-α. Banked autologous leukemic cells could be used for vaccination of CML patients in order to enhance anti-leukemia T cell responses and may, in combination with imatinib, lead to eradication of residual leukemic cells with a durable cure.
STAT3: A Direct HMGA1 Gene Target Important in Lymphoid Malignancy.
Authors: Resar Linda , Dhara Surajit , Sumter Takita Felder , Mukherjee Mita , Turkson James , Jove Rich , Elbahloul Ossama , Aplan Peter , Lin Ying-Wei , Bhattacharya Raka 
Published: October 2019

Abstract
While the oncogenic properties of the high mobility group A1 (HMGA1) gene are well established, the molecular pathways that mediate transformation by HMGA1 have not been clearly defined. HMGA1 is widely overexpressed in hematologic malignancies and other human cancers. Moreover, its overexpression portends a poor prognosis in some tumors. The HMGA1 gene encodes the HMGA1a and -A1b chromatin binding proteins. We previously showed that overexpression of HMGA1a or -A1b confers a transformed phenotype in cultured, human lymphoid cells. More recently, we developed transgenic mice overexpressing HMGA1a and all mice develop aggressive lymphoid malignancy. Because HMGA1 proteins function in regulating gene expression, we hypothesize that overexpression of HMGA1 leads to neoplastic transformation by altering expression of specific target genes involved in this process. To identify genes that are regulated by HMGA1 in transformation, we used microarray gene expression profile analysis in cells transfected to overexpress HMGA1a or -A1b. Ninety-seven genes were differentially regulated by ≥ 2-fold in cells overexpressing HMGA1a and 103 genes were differentially regulated by ≥ 2-fold in cells overexpressing HMGA1b. Fifty-five of these genes were common to both the HMGA1a and -A1b cells. From the list of genes up-regulated in cells overexpressing HMGA1a or A1b, the gene encoding the signaling molecule, signal transducer and activator of transcription or STAT3, was studied further because of its prominent role in malignancy. HMGA1 binds to the STAT3 promoter in human leukemia cells in vivo by chromatin immunoprecipitation experiments and enhances transcription of the STAT3 promoter in transfection experiments. Both total STAT3 and activated STAT3 proteins are increased in leukemia cells from HMGA1a transgenic mice compared to lymphoid cells from control mice. Moreover, activated STAT3 recapitulates the transforming activity of HMGA1a in cultured cells. Blocking STAT3 function preferentially induces apoptosis in leukemia cells from HMGA1a transgenic mice, but not in control cells. STAT3 mRNA is also increased in human acute lymphoid leukemia samples that overexpress HMGA1a, suggesting that this pathway is also involved in human lymphoid leukemia. Our results indicate that STAT3 is a direct HMGA1a target gene that is both necessary and sufficient for transformation induced by HMGA1a.