scholarly journals MLL5 improves ATRA driven differentiation and promotes xenotransplant engraftment in acute promyelocytic leukemia model

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Diego A. Pereira-Martins ◽  
Isabel Weinhäuser ◽  
Juan Luiz Coelho-Silva ◽  
Pedro L. França-Neto ◽  
Luciana Y. Almeida ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Critical Role ◽  
In Silico Analysis ◽  
Underlying Mechanism ◽  
Leukemic Cells ◽  
Granulocytic Differentiation ◽  
Drug Induced ◽  
Downstream Signaling ◽  
Epigenetic Modifiers ◽  
Induced Apoptosis

AbstractAlthough the mixed lineage leukemia 5 (MLL5) gene has prognostic implications in acute promyelocyte leukemia (APL), the underlying mechanism remains to be elucidated. Here, we demonstrate the critical role exerted by MLL5 in APL regarding cell proliferation and resistance to drug-induced apoptosis, through mtROS regulation. Additionally, MLL5 overexpression increased the responsiveness of APL leukemic cells to all-trans retinoic acid (ATRA)-induced differentiation, via regulation of the epigenetic modifiers SETD7 and LSD1. In silico analysis indicated that APL blasts with MLL5high transcript levels were associated with retinoic acid binding and downstream signaling, while MLL5low blasts displayed decreased expression of epigenetic modifiers (such as KMT2C, PHF8 and ARID4A). Finally, APL xenograft transplants demonstrated improved engraftment of MLL5-expressing cells and increased myeloid differentiation over time. Concordantly, evaluation of engrafted blasts revealed increased responsiveness of MLL5-expressing cells to ATRA-induced granulocytic differentiation. Together, we describe the epigenetic changes triggered by the interaction of MLL5 and ATRA resulting in enhanced granulocytic differentiation.

scholarly journals c-sis but not c-fos gene expression is lineage specific in human myeloid cells

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 488-493
Author(s):  
E Sariban ◽  
T Mitchell ◽  
A Rambaldi ◽  
DW Kufe
Keyword(s):  
Gene Expression ◽  
Leukemic Cells ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Drug Induced ◽  
Monocytic Cells ◽  
Hexamethylene Bisacetamide ◽  
Gene Transcripts ◽  
Myelomonocytic Leukemia ◽  
Monocytic Lineage

Expression of both the c-fos and c-sis protooncogenes during myeloid differentiation has been detected in cells of the monocytic lineage. Since an increase in c-fos transcripts was not detected during dimethylsulfoxide induced HL-60 granulocytic differentiation, it was suggested that within the myeloid series c-fos gene expression might be lineage specific. In the present study, we have determined whether expression of the c-fos and c-sis genes is indeed specific for the monocytic pathway or rather common to both the granulocyte and monocyte pathways. C-fos and c-sis gene expression was analyzed in freshly isolated human granulocytes and monocytes, in human HL-60 promyelocytic leukemia cells induced to differentiate along the granulocytic or monocytic pathway, in myeloblasts from five patients with the M1 or M2 subtype of acute myeloblastic leukemia (AML) and in blasts from six patients with M4 myelomonocytic leukemia. The level of c-fos mRNA was fifteen times higher in granulocytes as compared with monocytes. An increase in c-fos expression was also found in HL-60 cells differentiated along the granulocytic pathway after exposure to hypoxanthine, hexamethylene bisacetamide, and the combination of retinoic acid and dibutyryl adenosine 3′5′ cyclic monophosphate. Three of 5 M1 and M2 leukemic myeloblast preparations depleted of lymphoid and monocytic cells and all six M4 leukemic cells expressed c-fos transcripts. In contrast, c-sis gene transcripts were detectable in monocytes and during drug induced monocytic differentiation of the HL- 60 cells but not in granulocytes during granulocytic differentiation of the HL-60 cells or in AML samples. Thus, in the myeloid series, c-sis gene expression is lineage specific while expression of the c-fos gene is found in both lineages and may be related to metabolic pathways common to both granulocytes and monocytes.

C/EBPδ Modulates Cell Growth, Differentiation and Apoptosis of Myeloid Leukemia, Prostate and Breast Cancer Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4300-4300
Author(s):  
Sigal Gery ◽  
Sakae Stanosaki ◽  
Takayuki Ikezoe ◽  
Wolf K. Hofmann ◽  
Adrian F. Gombart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Myeloid Leukemia ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Leukemic Cells ◽  
Granulocytic Differentiation ◽  
Mcf 7

Abstract C/EBPδ belongs to the family of highly conserved CCAAT/enhancer binding protein (C/EBP) transcription factors. Members of this family play a critical role in the regulation of mitotic growth arrest and differentiation in numerous cell types. To examine the consequences of C/EPBδ expression, we transfected C/EPBδ into CML myeloid leukemia (KCL22, K562), prostate (LNCaP, PC3, DU145), and breast (MCF-7, T47D, MDA-MB-231) cancer cell lines. C/EBPδ expression resulted in a proliferative arrest and an increase in apoptosis of the myeloid leukemia cells, as well as the prostate cells LNCaP and PC3, and the breast cells MCF-7 and T47D. In contrast, DU145 prostate and MDA-MB-231 breast cancer cells were not inhibited by C/EBPδ, indicating that the biologically properties of C/EBPδ depend upon its cellular context. We further studied the molecular mechanisms underlying the affect of C/EPBδ expression in CML leukemic cells. Myeloid differentiation of KCL22 and K562 blast cells as shown by morphologic changes and induction of secondary specific granule genes, occurred within 4 days of inducing expression of C/EBPδ. Furthermore, expression of C/EBPδ was associated with downregulation of c-Myc and cyclin E, and upregulation of the forkhead transcription factor FoxO1a (FKHR) and the cyclin-dependent kinase inhibitor p27Kip1. In addition, microarray analysis showed that C/EBPδ mRNA is upregulated during granulocytic differentiation of normal CD34+ bone marrow cells, suggesting that C/EBPδ is involved in lineage-specific differentiation. Taken together, these results show that expression of C/EBPδ in BCR-ABL-positive CML cells in blast crisis, is sufficient for neutrophil differentiation and suggest that ectopic induction of C/EBPδ in the blastic phase of CML, as well as in certain cases of prostate and breast cancers, may hold promising therapeutic potential.

Role of Erythropoietin Receptor in t(12;21) Positive Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2792-2792
Author(s):  
Renate Panzer-Gruemayer ◽  
Gerd Krapf ◽  
Dominik Beck ◽  
Gerhard Fuka ◽  
Christian Bieglmayer ◽  
...  
Keyword(s):  
Cell Lines ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Erythropoietin Receptor ◽  
Molecular Signature ◽  
Leukemic Cells ◽  
Drug Induced ◽  
Induced Apoptosis

Abstract The chromosomal translocation t(12;21)(p13;q22) resulting in the TEL/AML1 (also known as ETV6/ RUNX1) fusion gene is the most frequent translocation in childhood B cell precursor (BCP) ALL. This type of ALL is characterized by a unique molecular signature, which includes the overexpression of the gene for the erythropoietin receptor (EpoR). So far, it is not known what causes the overexpression of the EpoR gene or whether it has any effect on the t(12;21) positive leukemia. We therefore aimed to evaluate potential mechanisms responsible for the upregulation of the EpoR in t(12;21) leukemias and to find out whether signalling via this receptor affects survival or proliferation of leukemic cells. In addition, we planned to explore signalling pathways linked to the respective effects and to elucidate relevant mechanisms that might be essential for cell survival. We first excluded the possibility that the EpoR expression is upregulated as a consequence of high Epo levels in the plasma that are induced by the patients’ low hemoglobin (Hb) levels. While Hb levels from patients with t(12;21)+ ALL were significantly lower compared to those with other subtypes of BCP ALL (median, 6,15g/dL and 7,9g/dL, respectively; p<0.001 Wilcoxon 2- sample test), which correlated with high Epo levels in the plasma, the extent of EpoR mRNA expression of leukemic cells was independent of the respective amount of Epo in the individual patient’s plasma. Next, the influence of Epo on t(12;21) + leukemic cell lines was evaluated and revealed a consistent time and dose dependent increase in proliferation (Epo concentrations 10, 50, 100U/ml for 72 hours) determined by 3H-Thymidine incorporation. This effect was abrogated upon addition of a blocking anti-EpoR antibody thereby confirming the specificity of EpoR signalling. Since Epo may have apoptosis-modulating potential in EpoR expressing malignant cells, we tested its influence on drug-induced apoptosis. For this purpose IC50 concentrations of drugs that are commonly used for the treatment of children with BCP ALL were used. A reduction of glucocorticoid (GC)-induced apoptosis by Epo was demonstrated in t(12;21)+ cell lines while no effect was seen in combination with other drugs or in t(12;21) negative cell lines. Preliminary data indicate that NF-kappa B as well as PI3K/Akt pathways are triggered by Epo, implying that they play a role in this rescue mechanism. Given that cell lines may have intrinsic changes, we are presently evaluating whether the observed results can also be reproduced in primary leukemic cells. In support of this assumption are results in a limited number of primary t(12;21)+ leukemias showing a superior survival (MTT assay) and reduced apoptosis rate to GC when cultured in the presence of Epo. These findings are in contrast to those in t(12;21) negative BCP ALLs. In conclusion, our data indicate that overexpression of EpoR in t(12;21) positive leukemias is not induced by low Hb, a feature that is generally observed in patients with this type of leukemia. Binding of Epo to its receptor in vitro leads to enhanced survival and negatively affects the sensitivity to GCs. Whether these findings have any implications on the treatment and care of patients with t(12;21)+ leukemia needs to be addressed in further studies. Financial support: OENB10720, FWF P17551-B14 and GENAU-CHILD Projekt GZ200.136/1 - VI/1/2005 to RPG.

Trans-Cinnamaldehyde Induces Granulocytic Differentiation and Impairs Survival and Migration of Acute Myeloid Leukemic Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5035-5035
Author(s):  
Liqiong Liu ◽  
Ping Wang ◽  
Xingbin Wang ◽  
Junxia Gu ◽  
Xiaoqing Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Leukemic Cells ◽  
Migration And Invasion ◽  
Granulocytic Differentiation ◽  
Hl60 Cells ◽  
Hematopoietic Malignancies ◽  
Cd34 Cells ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract Trans-cinnamaldehyde (TCA), the major active component of oil isolated from the stem bark of Cinnamomum cassia traditionally used to treat dyspepsia, gastritis and inflammatory disease world widely, has been shown to inhibit proliferation and promote apoptosis in a number of cancer cells. However, the functional roles TCA plays in hematopoietic system have not been fully investigated. In this study, we show the effects of TCA on acute promyelocytic leukemia (APL) cell line HL60 and primary bone marrow mononuclear cells (BMMNC) as well as bone marrow stromal cells (BMSC) from acute myeloid leukemia (AML) patients. We found that TCA affected HL60 cells in a time-and dose-dependent fashion. Low concentration of TCA (20 μM) arrested HL60 cells at G0/G1 phase at 72 h without significant apoptosis. Middle concentration of TCA (60 μM) accumulated HL60 cells at G2/M at 24 h with increased apoptosis when the treated time was prolonged. Both low and middle concentrations of TCA induced HL60 cells to differentiate toward mature granule cells characterized with up-regulation of CD11b on cells accompanied by decreased c-Myc protein and increased p27 protein. Consistently, the expression and cellular distribution of p16 and Cdc6 were also significantly changed in differentiated HL60 cells treated with TCA. On the other hand, high concentration of TCA (100 μM) rapidly inhibited NF-kappaB activity and induced apoptosis in HL60 cells. Importantly, TCA induced apoptosis of AML CD34+ cells and suppressed colony formation of AML BMMNC, while its cytotoxicity on normal BMMNC was minor. In addition, TCA synergized with AraC to kill AML BMMNC and AML CD34+ cells. Finally, TCA also decreased CXCR4 expression on HL60 cells, consistent with it ability to depress migration and invasion of HL60 cells induced by rhSDF-1α as well as the adhesion of HL60 cells to AML BMSC. Of note, TCA also impaired survival and SDF-1α secretion of AML BMSC, which may further suppress the interaction of HL60 with AML BMSC. Taken together, our data show that TCA is an effective agent for the treatment of hematopoietic malignancies, not only being the direct inducer of terminal differentiation and apoptosis of acute myeloid leukemic cells, but attenuating the protective effect of AML BMSC on leukemia cells via inhibiting SDF-CXCR4 axis, which highlights the potential of TCA to be a promising therapeutic agent for hematopoietic malignancies treatment.

scholarly journals Autophagy Activation Induces Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia with FLT3-ITD Mutation

2021 ◽  
Author(s):  
Dan Xu ◽  
Zhao Yin ◽  
Ying Yang ◽  
Yishan Chen ◽  
Changfen Huang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Leukemic Cells ◽  
Sorafenib Treatment ◽  
Downstream Signaling ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Inhibitor Resistance ◽  
Acute Myeloid

Abstract Background: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. Methods: We detected the alteration of autophagy in FLT3-ITD-positive leukemic cells after versus before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. Results: Sorafenib-resistant cells markedly overexpressed autophagy in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to induce FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame FLT3 inhibitor resistance. Conclusions: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance.

scholarly journals Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid

Blood ◽  
1981 ◽  
Vol 57 (6) ◽  
pp. 1000-1004 ◽  
Author(s):  
TR Breitman ◽  
SJ Collins ◽  
BR Keene
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Leukemia Cell ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cell Line ◽  
Granulocytic Differentiation ◽  
Myelocytic Leukemia ◽  
Functional Maturation ◽  
Promyelocytic Leukemia Cell Line

The recent finding that retinoic acid induces terminal granulocytic differentiation of the human promyelocytic leukemia cell line, HL-60, prompted an investigation of the sensitivity to this inducer of human myelocytic leukemia cells in primary suspension culture. Of the 21 leukemic specimens, only cells from the two patients with acute promyelocytic leukemia differentiated in response to retinoic acid. After an incubation period of 5--7 days in 1 microM retinoic acid, the cells from these two patients showed extensive morphological and functional maturation. Thus, because it appears that retinoic acid specifically induces granulocytic differentiation of leukemic promyelocytes, this compound may have therapeutic utility in the treatment of acute promyelocytic leukemia.

Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid–mediated transactivation is dispensable

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1541-1550 ◽  
Author(s):  
Scott C. Kogan ◽  
Suk-hyun Hong ◽  
David B. Shultz ◽  
Martin L. Privalsky ◽  
J. Michael Bishop
Keyword(s):  
Retinoic Acid ◽  
Transgenic Mice ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Chromosomal Translocation ◽  
Leukemic Cells ◽  
Leukemic Transformation ◽  
Variable Effect ◽  
Acid Therapy

The most common chromosomal translocation in acute promyelocytic leukemia (APL), t15;17(q22;q21), creates PMLRAR andRARPML fusion genes. We previously developed a mouse model of APL by expressing PMLRAR in murine myeloid cells. In order to examine the mechanisms by which PMLRAR can initiate leukemia, we have now generated transgenic mice expressingPMLRARm4 and RARm4, proteins that are unable to activate transcription in response to retinoic acid.PMLRARm4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRAR is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARm4 transgenic mice varied from those previously observed in our PMLRAR transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARm4transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through thePMLRAR protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARm4 have not developed leukemia, providing evidence that the PML domain ofPMLRAR plays a specific and critical role in the pathogenesis of APL.

Death Associated Protein 5 (DAP5/p97/NAT1) Contributes to Retinoic Acid-Induced Granulocytic Differentiation and Arsenic Trioxide Induced Apotosis through Inhibition of PI3K/Akt/mTOR Pathway in Acute Promyelocytic Leukemia Cells: A Novel Mechanism.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2836-2836
Author(s):  
Bulent Ozpolat ◽  
Ugur Akar ◽  
Isabel Zorilla-Calancha ◽  
Pablo Vivas-Mejia ◽  
Gabriel Lopez-Berestein
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Translation Initiation ◽  
Promyelocytic Leukemia ◽  
Mtor Pathway ◽  
Granulocytic Differentiation ◽  
Induced Expression ◽  
Nb4 Cells ◽  
Induced Apoptosis

Abstract All-trans Retinoic Acid (ATRA) is a naturally occurring metabolite of retinol (vitamin A)and acts as a potent inducer of cellular differentiation and growth arrest in acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (M3-AML). APL is characterized by translocation t(15;17), fusing PML (promyelocytic leukemia) and RARα (retinoic acid receptor) genes, leding to expression of PML/RARα receptor protein and differentiation block. Arsenic trioxide (ATO) induces (<0.5 μM) differentiation at low doses and apoptosis at high doses (>1 μM) in APL cells. Currently, both ATRA and ATO are successfully used in the treatment of APL in the clinic. However, the molecular mechanisms of myeloid differentiation and apoptosis induced by these agents are not fully understood. We previously reported that ATRA inhibits the translation initiation through multiple mechanisms, including upregulation of translation initiation inhibitors, DAP5/p97 and PDCD4 tumor suppressor protein. Here we investigated the role and regulation of death associated protein-5 (DAP5/p97/NAT1), a novel inhibitor of translational initiation, in myeloid (granulocytic and monocytic) cell differentiation and apoptosis. We found that ATRA (1 μM) induced a marked DAP5/p97 protein and mRNA expression during granulocytic differentiation of NB4 and HL60 cells but not in differentiation-resistant cells, which express very low levels of DAP5/p97. DAP5/p97 was translocated into nucleus during the differentiation of NB4 cells induced ATRA. At differentiation inducing doses, ATO, dimethysulfoxide, 1,25-dihydroxy-vitamin-D3, and phorbol-12-myristate-13-acetate also induced a significant DAP5/p97 expression in NB4 cells. However, ATO at apoptotic doses, but not ATRA, induced DAP5/p86, a proapoptotic form of DAP5/p97. ATRA and ATO -induced expression of DAP5/p97 was associated with inhibition of phosphaditylinositol 3-kinase (PI3K)/Akt pathway, which is known to stimulate cap-dependent translation of mRNAs. To show direct link between PI3K/Akt/mTOR pathway and DAP5 expression, we treated cell with PI3K and mTOR inhibitors LY294002 and by rapamycin, respectively. We found that inhibition of PI3K/Akt/mTOR pathway upregulated DAP5/p97 expression in NB4 cells. Finally, knockdown of DAP5/p97 expression by small interfering RNA significantly inhibited ATRA-induced granulocytic differentiation detected by expression of CD11b and ATO-induced apoptosis in NB4 cells detected by Annexin V assay (p<0.05). In conclusion, our data suggest that DAP5/p97 plays a role in ATRA-induced differentiation and ATO-induced apoptosis in APL cells. Our data demonstrated for the first time that DAP5/p97 is constitutively suppressed by of PI3K/Akt/mTOR pathway, and ATRA and ATO-induced expression of DAP5 is mediated by the inhibition of this survival pathway, suggesting a novel mechanism of DAP5 regulation and a role of translational control in induction of differentiation and apoptosis. Figure Figure

Cooperation Between the CD20 Receptor and hIFN-Alpha Receptor in Overriding the Blocked CD20 Cell-Signaling in Rituximab-Resistant B-NHL By the Fusion Protein Anti-CD20-hIFN-Alpha

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1468-1468
Author(s):  
Gabriel G Vega ◽  
Luz A Franco-Cea ◽  
Sara Huerta-Yepez ◽  
Hector Mayani ◽  
Otoniel Martinez-Maza ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Cell Signaling ◽  
Cell Survival ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Specific Inhibitor ◽  
Underlying Mechanism ◽  
Drug Induced ◽  
Drug Sensitization ◽  
Induced Apoptosis

Abstract Introduction: The standard treatment of B-NHL consists of rituximab in combination with CHOP (RCHOP) and results in a significant clinical response. Rituximab inhibits cell-proliferation and inhibits cell survival/anti-apoptic signaling pathways. A subset of patients does not initially respond and a subset of responding patients develops resistance to RCHOP. The genetic engineering of a fusion protein, α-CD20-hIFN-α, was found to be active in the rituximab-resistant B-NHL cell lines. Objective: To investigate the underlying mechanism by which α-CD20-hIFN-α signals in the resistant lines. Hypothesis: We hypothesized that the treatment with the α-CD20-hIFN-α may result in the cooperation of both α-CD20 and hIFN-α and their interactions with corresponding receptors that will result in overriding α-CD20 blocked cell signaling. Methods: Rituximab-resistant cell lines, R-2F7 and R-Ramos, were used as models. Cell signaling was determined by western. Sensitivity to drug-induced apoptosis was done by activation of caspase 3 by flow cytometry. Results: Treatment of the R lines with α-CD20-hIFN-α resulted in the inhibition of cell growth and sensitization to doxorubicin-induced apoptosis. Treatment with single agents alone or combination was not effective. Treatment with the α-CD20-hIFN-α resulted in the inhibition of the NFκB and the p38 MAPK pathways. In addition, the hIFN-mediated signaling pathway, namely, PKC-d, was also inhibited by the α-CD20-hIFN-α.The role of PKC-d in drug sensitization was corroborated by the use of the specific inhibitor, Rotterin, which reversed the drug sensitization by α-CD20-hIFN-α and doxorubicin Conclusion: The ability of the α-CD20-hIFN-α to inhibit cell survival and anti-apoptotic pathways, that was not achieved with single agents or combination, suggested that there may be a crosslinking of the CD20 and hIFN-α receptors by α-CD20-hIFN-α and results in triggering the cells via both receptors and inhibiting intracellular survival pathways and sensitization to drug apoptosis. Clinical Implication: The findings also suggest the potential therapeutic application of the combination of α-CD20-hIFN-α and drugs for the treatment of patients resistant to RCHOP. Disclosures No relevant conflicts of interest to declare.

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