WEE1 and PARP-1 play critical roles in myelodysplastic syndrome and acute myeloid leukemia treatment.

BACKGROUND: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder defined by cytopenia and is associated with an increased risk of transformation to acute myeloid leukemia (AML). The outcome of MDS is poor, so alternative therapeutic approaches are needed to improve survival. The inhibition of the DNA damage response pathway, including poly (ADP-ribose) polymerase-1 (PARP-1), has been approved to treat several cancers. In addition, WEE1, a nuclear kinase, is overexpressed in many cancers. Therefore, a WEE1 inhibitor combined with a PARP-1 inhibitor could inhibit the proliferation of MDS and AML. METHODS: We analyzed whether WEE1 was regulated in the progression of MDS and AML. We also evaluated the efficacy of MK-1775 (WEE1 inhibitor) and talazoparib (PARP-1 inhibitor). RESULTS: PARP-1 expression was higher in the AML cells than in the MDS cells. However, WEE1 expression remained unchanged. MK-1775 or talazoparib alone inhibited MDS and AML cells after 72 h, and cellular cytotoxicity and caspase 3/7 activity were increased. The combined use of MK-1775 and talazoparib produced superior efficacy than either drug alone and SKM-1 colony formation was reduced. Significant cell populations in the sub-G1 phase were found in the cell-cycle analyses. Additionally, γ-H2AX expression and caspase 3 activity were increased. The combined treatment also changed the mitochondrial membrane potential. CONCLUSIONS: The combination of a WEE1 inhibitor and PARP-1 inhibitor had enhanced efficacy and is proposed as a new therapeutic option for patients with MDS or AML. Our findings have clinical implications for a potential novel therapeutic strategy for MDS and AML patients.

Effect of asciminib and vitamin K2 on Abelson tyrosine-kinase-inhibitor-resistant chronic myelogenous leukemia cells.

BACKGROUND: Abelson (ABL) tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML); however, many patients develop resistance during ABL TKI therapy. Vitamin K2 (VK2) is a crucial fat-soluble vitamin used to activate hepatic coagulation factors and treat osteoporosis. Although VK2 has demonstrated impressive anticancer activity in various cancer cell lines, it is not known whether VK2 enhances the effects of asciminib, which specifically targets the ABL myristoyl pocket (STAMP) inhibitor. METHOD: In this work, we investigated whether VK2 contributed to the development of CML cell lines. We also investigated the efficacy of asciminib and VK2 by using K562, ponatinib-resistant K562 (K562 PR), Ba/F3 BCR-ABL, and T315I point mutant Ba/F3 (Ba/F3 T315I) cells. RESULTS: Based on data from the Gene Expression Omnibus (GEO) database, gamma-glutamyl carboxylase (GGCX) and vitamin K epoxide reductase complex subunit 1 (VKORC1) were elevated in imatinib-resistant patients (GSE130404). UBIA Prenyltransferase Domain Containing 1 (UBIAD1) was decreased, and K562 PR cells were resistant to ponatinib. In contrast, asciminib inhibited CML cells and ponatinib resistance in a dose-dependent manner. CML cells were suppressed by VK2. Caspase 3/7 activity was also elevated, as was cellular cytotoxicity. Asciminib plus VK2 therapy induced a significantly higher level of cytotoxicity than use of each drug alone. Asciminib and VK2 therapy altered the mitochondrial membrane potential. CONCLUSIONS: Asciminib and VK2 are suggested as a novel treatment for ABL-TKI-resistant cells since they increase treatment efficacy. Additionally, this treatment option has intriguing clinical relevance for patients who are resistant to ABL TKIs.

[Desquamative esophagitis associated with unrelated allogeneic peripheral blood stem cell transplantation using the FBM conditioning regimen].

Desquamative esophagitis (DE) is a rare benign condition characterized by sheet-like shedding of esophageal squamous epithelial tissue. Although cases of drug-induced DE, such as those induced by direct oral anticoagulants, have been reported, cases of DE complicated with hematopoietic stem cell transplantation (HSCT) are rare. We herein report the case of a 52-year-old woman with FLT3-ITD mutation-positive acute myeloid leukemia who presented with DE immediately after HSCT. Allogeneic peripheral blood HSCT with FBM (fludarabine 180 mg/m2, busulfan 12.8 mg/m2, and melphalan 80 mg/m2) was performed during the first remission. Tacrolimus plus short-term methotrexate was planned for graft-versus-host disease prevention. Common Terminology Criteria for Adverse Events grade 3 equivalent vomiting was observed during treatment with the conditioning regimen. On day 5 after HSCT, a white band of 10 cm in length and 1 cm in width was discharged from the oral cavity during vomiting. Upper gastrointestinal endoscopy revealed mucosal detachment in the entire esophagus and the diagnosis of DE was made. DE improved on providing conservative treatment. We concluded that the mechanical pressure that developed on the esophagus due to frequent vomiting contributed to the mucosal detachment owing to regimen-related toxicity. Even in the FBM regimen, which is widely used as a conditioning regimen, caution is required to prevent DE.

Copanlisib, a novel phosphoinositide 3-kinase inhibitor, combined with carfilzomib inhibits multiple myeloma cell proliferation.

Multiple myeloma (MM) is a uniformly fatal disorder of B cells characterized by the accumulation of abnormal plasma cells. Phosphoinositide 3-kinase (PI3K) signaling pathways play a critical regulatory role in MM pathology. Copanlisib, also known as BAY80-6946, is a potent PI3Kα and δ inhibitor. In this study, we investigated the efficacy of copanlisib and a proteasome inhibitor using MM cell lines and primary samples. The p110α and δ catalytic subunits of the class PI3K increased, and carfilzomib activity reduced in the presence of a supernatant from the feeder cell line, HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) partially reduced upon carfilzomib treatment in the presence of HS-5. Apoptosis also decreased. Copanlisib treatment for 72 h inhibited growth in MM cell lines and induced apoptosis. Combination treatment of MM cells with carfilzomib and copanlisib caused greater cytotoxicity than that caused by either drug alone and increased apoptosis. Caspase 3 activity increased while that of Akt decreased after combination treatment with copanlisib and carfilzomib. Further, copanlisib inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in vitro and in vivo. It also inhibited C-X-C motif chemokine 12 (CXCL12)-mediated chemotaxis. The data suggest that administration of the PI3K inhibitor, copanlisib, may be a powerful strategy against stroma-associated drug resistance of MM cells and can enhance the cytotoxic effects of proteasome inhibitors in such residual MM cells.

BCR-ABL1-positive chronic myeloid leukemia emerging in a patient with secondary myelofibrosis harboring the JAK2-V617F mutation.

A 53-year-old woman with a 27-year history of myeloproliferative neoplasms came to our hospital because of a marked white blood cell count increase and progressive anemia. Clinical examination demonstrated positivity for BCR-ABL1 and JAK2-V617F mutations. She was given a diagnosis of chronic myeloid leukemia. Using the international scale, a molecular response (MR) 4.5 was achieved after treatment with dasatinib, despite the persistence of marked splenomegaly. The pathological findings of myelofibrosis were demonstrated by bone marrow biopsy. After stopping dasatinib administration for 4 years and 5 months, treatment with ruxolitinib was started. Five months later, the size of her spleen was reduced. We speculated that translocation of BCR-ABL1 might have occurred in a sub-clone of the JAK2-V617F mutated tumor clone.

Downregulation of Plasma miR-215 in Chronic Myeloid Leukemia Patients with Successful Discontinuation of Imatinib.

Approximately 40% of chronic myeloid leukemia (CML) patients who discontinue imatinib (IM) therapy maintain undetectable minimal residual disease (UMRD) for more than one year (stopping IM (STOP-IM)). To determine a possible biomarker for STOP-IM CML, we examined plasma miRNA expression in CML patients who were able to discontinue IM. We first screened candidate miRNAs in unselected STOP-IM patients, who had sustained UMRD after discontinuing IM for more than six months, in comparison with healthy volunteers, by using a TaqMan low-density array for plasma or exosomes. Exosomal miR-215 and plasma miR-215 were downregulated in the STOP-IM group compared to the control, indicating that the biological relevance of the plasma miR-215 level is equivalent to that of the exosomal level. Next, we performed real-time quantitative RT-PCR in 20 STOP-IM patients, 32 patients with UMRD on continued IM therapy (IM group) and 28 healthy volunteers. The plasma miRNA-215 level was significantly downregulated in the STOP-IM group (p < 0.0001); we determined the cut-off level and divided the IM group patients into two groups according to whether the plasma miR-215 was downregulated or not. The IM group patients with a low plasma miR-215 level had a significantly higher total IM intake, compared to the patients with elevated miR-215 levels (p = 0.0229). Functional annotation of miR-215 target genes estimated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools involved cell cycle, mitosis, DNA repair and cell cycle checkpoint. Our study suggests a possible role of miR-215 in successful IM discontinuation.

Musculoskeletal pain after stopping tyrosine kinase inhibitor in patients with chronic myeloid leukemia: a questionnaire survey.

We conducted a questionnaire survey to assess the state of patients with CML after discontinuation of TKI therapy. Nine of 27 patients developed musculoskeletal pain after TKI discontinuation. One had discontinued nilotinib and eight had discontinued imatinib therapy. Median time to symptom development after discontinuation was 2 weeks. Four experienced grade 3 symptoms as per the CTCAE ver. 4.0. One had pain persisting over a period of 21 months. There was a significant difference between patients with and without symptoms as regards female gender and the probability of persistent MMR. Awareness of this withdrawal syndrome after TKI discontinuation is imperative.

[Treatment-free molecular remission achieved by combination therapy with imatinib and IFNα in CML with BIM deletion polymorphism relapsed after stop imatinib].

A 51-year-old man with chronic myeloid leukemia (CML) was treated with imatinib (IM). After 24 months of treatment, he achieved a complete molecular response (CMR), which he sustained for 3 years. However, 4 months after discontinuing IM treatment, the CML relapsed. The patient was treated again with IM and achieved CMR. A combination of IM and interferon-α (IFNα) was administered for the following year, and then discontinued. The patient has since sustained CMR without therapy for 24 months, to date. This patient was found to have a BCL2L11 (BIM) deletion polymorphism. CML patients with a BIM deletion polymorphism show a low response to IM, and we infer that the BIM deletion polymorphism is a negative factor for discontinuation of IM. IFNα treatment is expected to prevent relapse during immunological surveillance. Therefore, the combination of IM and IFNα might be a feasible approach for CML patients who experience difficulty with IM discontinuation.

Anti-leukemic potency of piggyBac-mediated CD19-specific T cells against refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND AIMS: To develop a treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant to tyrosine kinase inhibitors (TKIs), we evaluated the anti-leukemic activity of T cells non-virally engineered to express a CD19-specific chimeric antigen receptor (CAR). METHODS: A CD19.CAR gene was delivered into mononuclear cells from 10 mL of blood of healthy donors through the use of piggyBac-transposons and the 4-D Nucleofector System. Nucleofected cells were stimulated with CD3/CD28 antibodies, magnetically selected for the CD19.CAR, and cultured in interleukin-15-containing serum-free medium with autologous feeder cells for 21 days. To evaluate their cytotoxic potency, we co-cultured CAR T cells with seven Ph(+)ALL cell lines including three TKI-resistant (T315I-mutated) lines at an effector-to-target ratio of 1:5 or lower without cytokines. RESULTS: We obtained ∼1.3 × 10(8) CAR T cells (CD4(+), 25.4%; CD8(+), 71.3%), co-expressing CD45RA and CCR7 up to ∼80%. After 7-day co-culture, CAR T cells eradicated all tumor cells at the 1:5 and 1:10 ratios and substantially reduced tumor cell numbers at the 1:50 ratio. Kinetic analysis revealed up to 37-fold proliferation of CAR T cells during a 20-day culture period in the presence of tumor cells. On exposure to tumor cells, CAR T cells transiently and reproducibly upregulated the expression of transgene as well as tumor necrosis factor-related apoptosis-inducing ligand and interleukin-2. CONCLUSIONS: We generated a clinically relevant number of CAR T cells from 10 mL of blood through the use of piggyBac-transposons, a 4D-Nulcleofector, and serum/xeno/tumor cell/virus-free culture system. CAR T cells exhibited marked cytotoxicity against Ph(+)ALL regardless of T315I mutation. PiggyBac-mediated CD19-specific T-cell therapy may provide an effective, inexpensive and safe option for drug-resistant Ph(+)ALL.

Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells.

The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). However, resistance to ABL TKIs can develop in CML patients due to BCR::ABL1 point mutations and CML leukemia stem cell (LSC). Aurora kinases are essential kinases for cell division and regulate mitosis, especially the process of chromosomal segregation. Aurora kinase members also promote cancer cell survival and proliferation. This study analyzed whether aurora kinases were regulated in the progression of CML. It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. The expressions of AURKA and AURKB were higher in the CML cells compared with normal cells using a public database (GSE100026). Asciminib or LY3295668 alone inhibited CML cells after 72 h, and cellular cytotoxicity was increased. The combined use of Asciminib and LY3295668 increased superior efficacy compared with either drug alone. Colony formation was reduced by cotreatment with asciminib and LY3295668. In the cell-cycle analyses, LY3295668 induced G2/M arrest. Cell populations in the sub-G1 phase were observed when cotreating with asciminib and LY3295668. The combination treatment also changed the mitochondrial membrane potential. In addition, AURKA shRNA transfectant cells had increased asciminib sensitivity. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.

Characterization of Asciminib-Resistant Philadelphia Chromosome-Positive Cells.

Background: Asciminib is approved for treating patients with chronic-phase chronic myeloid leukemia who were previously treated with two or more tyrosine kinase inhibitors or those with T315I mutation. However, the mechanisms underlying asciminib resistance remain unclear. Methods: In this study, we established a new asciminib-resistant cell line. We examined BCR::ABL1 gene mutation analysis and the effects of conventional chronic myelogenous leukemia inhibitors. Results: Direct sequencing revealed Y139D and T315I mutations in asciminib-resistant cells. Ponatinib and omacetaxine were effective against asciminib-resistant cells. Conclusions: Y139D and T315I mutations are extremely resistant to asciminib. Ponatinib and omacetaxine show potential for treating asciminib-resistant chronic myeloid leukemia.

Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects.

Aim: This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma (MM) despite significant therapeutic advances and the introduction of novel agents. Our study focused on how myeloma cells mediate the metabolic pathways essential for survival. Therefore, we examined the role of glutaminolysis in this process. Methods: We investigated the role of glutaminolysis in myeloma cell growth. In addition, we analyzed the ability of CB-839 (telaglenastat), a glutaminase (GLS) inhibitor, to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase (HDAC) inhibitors. Results: Glutamate deprivation significantly reduced MM cell proliferation. We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls. CB-839 inhibits MM cell proliferation in a dose-dependent manner, resulting in enhanced cytotoxicity. Additionally, intracellular α-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration. Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity. Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results. Compared to control cells, these cells also showed increased sensitivity to panobinostat. Conclusion: Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.

Vitamin K2 sensitizes the efficacy of venetoclax in acute myeloid leukemia by targeting the NOXA-MCL-1 pathway.

Promising outcomes have been reported in elder patients with acute myeloid leukemia (AML) using combined therapy of venetoclax (VEN) and azacytidine (AZA) in recent years. However, approximately one-third of patients appear to be refractory to this therapy. Vitamin K2 (VK2) shows apoptosis-inducing activity in AML cells, and daily oral VK2 (menaquinone-4, GlakayR) has been approved for patients with osteoporosis in Japan. We observed a high response rate to AZA plus VEN therapy, with no 8-week mortality in the newly diagnosed AML patients consuming daily VK2 in our hospital. The median age of the patients was 75.9 years (range 66-84) with high-risk features. Patients received AZA 75 mg/m2 on D1-7, VEN 400 mg on D1-28, and daily VK2 45 mg. The CR/CRi ratio was 94.7% (18/19), with a CR rate of 79%. Complete cytogenetic CR was achieved in 15 of 19 (79%) patients, and MRD negativity in 2 of 15 (13%) evaluable CR patients. Owing to the extremely high response rate in clinical settings, we further attempted to investigate the underlying mechanisms. The combination of VK2 and VEN synergistically induced apoptosis in all five AML cell lines tested. VK2, but not VEN, induced mitochondrial reactive oxygen species (ROS), leading to the transcriptional upregulation of NOXA, followed by MCL-1 repression. ROS scavengers repressed VK2 induced-NOXA expression and led to the cancellation of pronounced apoptosis and the downregulation of MCL-1 by VK2 plus VEN. Additionally, knockdown and knockout of NOXA resulted in abrogation of the MCL-1 repression as well as enhanced cytotoxicity by the two-drug combination, indicating that VK2 suppresses MCL-1 via ROS-mediated NOXA induction. These data suggest that the dual inhibition of BCL-2 by VEN and MCL-1 by VK2 is responsible for the remarkable clinical outcomes in our patients. Therefore, large-scale clinical trials are required.

Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells.

Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance.

Activity of histone deacetylase inhibitors and an Aurora kinase inhibitor in BCR-ABL-expressing leukemia cells: Combination of HDAC and Aurora inhibitors in BCR-ABL-expressing cells.

BACKGROUND: The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. However, resistance to imatinib mediated by mutations in the BCR-ABL domain has become a major problem in the treatment of these patients. METHODS: In the present study, we examined the activity of histone deacetylase (HDAC) inhibitors in combination with an Aurora kinase inhibitor in BCR-ABL-expressing cells. RESULTS: We found the HDAC inhibitors vorinostat and/or pracinostat (SB939) induced apoptosis in BCR-ABL-expressing cells. Additionally, HDAC inhibitors reduced levels of Aurora A and B protein. An Aurora kinase inhibitor, tozasertib (VX-680), inhibited growth, promoted pro-apoptotic activity, reduced the phosphorylation of BCR-ABL and Crk-L, and activated caspase-3 and poly (ADP-ribose) polymerase (PARP) in BCR-ABL-positive cells. Moreover, after treatment with tozasertib, HDAC protein expression was decreased. Combination of vorinostat or pracinostat with tozasertib had a synergistic inhibitory effect on the proliferation of T315I cells. Phosphorylation of Crk-L decreased, and PARP activation increased after treatment with vorinostat or pracinostat and tozasertib. Moreover, combination of vorinostat or pracinostat and tozasertib significantly increased the extent of apoptosis in primary chronic myeloid leukemia cells. CONCLUSIONS: This study demonstrated that combination of HDAC and Aurora inhibitors was highly effective against BCR-ABL-expressing cells.

Effect of D-mannose on Philadelphia chromosome-positive leukemia cells.

BACKGROUND: Although Abelson (ABL) tyrosine kinase inhibitors (TKIs) have demonstrated potency against chronic myeloid leukemia (CML), resistance to ABL TKIs can develop in CML patients after discontinuation of therapy. OBJECTIVE: Glucose metabolism may be altered in CML cells because glucose is a key metabolite used by tumor cells. We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. METHODS: We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. RESULTS: Treatment with D-mannose for 72 h inhibited the growth of K562 cells. Combined treatment using ABL TKIs and D-mannose induced a significantly higher level of cytotoxicity in Philadelphia chromosome (Ph)-positive leukemia cells than in control cells. In the mouse model, severe toxicity was observed as evidenced by body weight loss in the ponatinib and D-mannose combination treatment groups. CONCLUSION: Our results indicate that metabolic reprogramming may be a useful strategy against Ph-positive leukemia cells. However, caution should be exercised during clinical applications.

Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions.

The treatment of multiple myeloma (MM) patients has been dramatically changed by the introduction of new agents; however, many patients relapse. Hypoxia is a critical component of the bone-marrow microenvironment. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) is responsible for maintaining cellular levels of fructose-2,6-bisphosphate, which regulates glycolysis. We found that the gene expressions of PFKFB3 and PFKFB4 were elevated under hypoxic conditions. Treatments with the PFKFB3 inhibitor, PFK158, and PFKFB4 inhibitor, 5MPN, were found to inhibit the growth of myeloma cells. The combined treatment of myeloma cells with carfilzomib and PFK158 or 5MPN was more cytotoxic than either drug alone. Caspase 3/7 activity and cellular cytotoxicity were also increased. In addition, the combined treatment was effective in the bortezomib-resistant cell line. Our data also suggest that administration of PFKFB3 and PFKFB4 inhibitors may be a powerful strategy against myeloma cells and to enhance the cytotoxic effects of proteasome inhibitors in hypoxic conditions.

Potential of a sphingosine 1-phosphate receptor antagonist and sphingosine kinase inhibitors as targets for multiple myeloma treatment.

Sphingosine 1-phosphate (S1P) is a bioactive lipid involved in cancer progression through its binding to S1P receptors (S1PRs). However, the association between multiple myeloma (MM) and S1P is unclear. The current study aimed to investigate the potential anti-cancer effects of fingolimod and sphingosine kinase (SK) inhibitors in myeloma cells and the effects of S1P-induced chemoresistance and neovascularization on MM cell proliferation. MM cell lines were treated with the S1PR1 antagonist fingolimod and the SK inhibitors ABC294640 and SK1-I, after which cell proliferation was measured. Protein expression was also assessed under each condition using immunoblotting. Serum S1P levels in patients with MM, monoclonal gammopathy of undetermined significance and healthy volunteers were assessed. Human umbilical vessel cells (HUVECs) were co-cultured with anti-S1P agents to assess the effect on cell migration. All treatments suppressed myeloma cell proliferation and caspase-3-mediated apoptosis by suppressing S1P activity. These findings suggest that S1P activation is associated with proliferation and survival for MM cells. S1P attenuated the proteosome inhibitor (PI) effect, while the anti-S1P agents recovered the effect. In addition, S1P promoted the migration and proliferation of HUVECs, whereas the S1P inhibitors reduced the influence of S1P. This study highlights the therapeutic potential of anti-S1P agents for MM treatment. Inhibition of S1P function may overcome resistance to PI developed by myeloma cells and inhibit the changes to the bone marrow microenvironment via neovascularization.

Tyrosine Kinase Inhibitors Do Not Promote a Decrease in SARS-CoV-2 Anti-Spike IgG after BNT162b2 Vaccination in Chronic Myeloid Leukemia: A Prospective Observational Study.

We performed a prospective observational study of chronic myeloid leukemia (CML) patients after anti-SARS-CoV-2 BNT162b2 vaccination (VC). In total, 32 CML patients with tyrosine kinase inhibitor (TKI) therapy, 10 CML patients with treatment-free remission, and 16 healthy subjects participated in the study. From April 2021 to September 2021, all cases (median age = 58 years) were vaccinated twice. Immunoglobulin G for SARS-CoV-2 spike protein (S-IgG) was measured at three timepoints (before the first VC, 1−5 weeks after the second VC (T1), and approximately 6 months after the second VC (T2)). S-IgG was not observed before the first VC in any participant. At T1, all cases had acquired S-IgG. There were no significant differences in S-IgG levels among groups. A paired sample comparison of median S-IgG titers between T1 and T2 in all groups showed a significant reduction in T2 S-IgG titers. There were no significant differences in S-IgG levels among groups. When all patients were analyzed, those aged ≥58 years had significantly lower S-IgG levels than those aged <58 years at T1. The BNT162b2 vaccine was highly effective in CML patients with or without TKIs, and S-IgG levels were as persistent as those in healthy individuals.

Targeting phosphoinositide 3-kinases and histone deacetylases in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a type of hematological malignancy affecting the functions of plasma cells. The treatment of MM patients has changed dramatically with the use of new agents. However, unfortunately, it is still incurable. Therefore, a new approach for treating MM is still needed to improve patient outcomes. METHODS: Because the histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) pathway is a key signal in cancer cell biology, we investigated whether dual HDAC and PI3K inhibitors could suppress the myeloma cells. RESULTS: Gene expression of HDACs is high in myeloma cells. CUDC-907, a dual inhibitor of PI3K and HDAC, inhibits HDAC activity. Akt activity and expression of BCL-XL, MCL-1, and NF-κB p65 were reduced by CUDC-907 in a dose-dependent manner. The number of apoptotic and caspase 3/7-positive cells also increased in the myeloma cells. Combined treatment of myeloma cells with carfilzomib and CUDC-907 increased cytotoxicity compared to that observed with each drug alone. CONCLUSIONS: Data from this study suggested that the administration of CUDC-907 might be a powerful strategy against myeloma cells, to enhance the cytotoxic effects of proteasome inhibitors.