- A phase Ib study of the combination of afatinib and ruxolitinib in EGFR mutant NSCLC with progression on EGFR-TKIs. [Journal Article]
- LCLung Cancer 2019; 134:46-51
- CONCLUSIONS: The combination of afatinib and ruxolitinib was tolerated by patients, with modest clinical activity observed in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).
- CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. [Journal Article]
- PlosPLoS One 2019; 14(7):e0220026
- Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in…
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy.
- Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling. [Journal Article]
- SCStem Cell Res Ther 2019 Jul 16; 10(1):210
- CONCLUSIONS: IFN-γ inhibited the proliferation of liver-derived HSPCs. IFN-γ also impaired the differentiation of long-term hematopoietic stem cells (LT-HSCs) into short-term hematopoietic stem cells (ST-HSCs) and multipotent progenitors (MPPs) and the process from LSK (Lineage-Sca-1+c-Kit+) cells to γδT cells. Importantly, we proposed that IFN-γ might inhibit the activation of notch signaling through the JAK/STAT signaling pathway and thus impair the differentiation process of mouse adult liver and BM hematopoietic stem cells.
- B-cell frequencies and immunoregulatory phenotypes in myeloproliferative neoplasms: influence of ruxolitinib, interferon-α2, or combination treatment. [Journal Article]
- EJEur J Haematol 2019 Jul 11
- CONCLUSIONS: B-cell frequency and phenotype were altered in MPN patients. Ruxolitinib therapy had marked effects on both frequency and phenotype. This article is protected by copyright. All rights reserved.
- Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. [Journal Article]
- HHaematologica 2019 Jul 11
- Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia. However, accurate blast-specific drug responses cannot be measured with homogeneous "ad…
Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia. However, accurate blast-specific drug responses cannot be measured with homogeneous "add-mix-measure" cell viability assays. In this study, we implemented a flow cytometry-based approach to simultaneously evaluate the ex vivo sensitivity of different cell populations in 34 primary acute myeloid leukemia samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in acute myeloid leukemia samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 acute myeloid leukemia showed high sensitivity to venetoclax. In contrast, differentiated monocytic cells abundantly present in M4/5 subtypes showed resistance to Bcl-2 inhibition, whereas immature blasts in the same samples were sensitive, highlighting the importance of blast-specific readouts. Accordingly, in the total mononuclear cell fraction the highest BCL2/MCL1 gene expression ratio was observed in M0/1 and the lowest in M4/5 acute myeloid leukemia. Of the seven tested drugs, venetoclax had the highest blast-specific toxicity, and combining venetoclax with either MEK inhibitor trametinib or JAK inhibitor ruxolitinib effectively targeted all venetoclax-resistant blasts. In conclusion, we show that ex vivo efficacy of targeted agents and particularly Bcl-2 inhibitor venetoclax is influenced by the cell type, and accurate blast-specific drug responses can be assessed with a flow cytometry-based approach.
- Intestinal Behçet's Disease with Primary Myelofibrosis Involving Trisomy 8. [Case Reports]
- AHActa Haematol 2019 Jul 10; :1-4
- Behçet's disease (BD) is a disorder characterized by systemic inflammation of multiple organs, including the intestines. Several studies have reported a relationship between myelodysplastic syndrome …
Behçet's disease (BD) is a disorder characterized by systemic inflammation of multiple organs, including the intestines. Several studies have reported a relationship between myelodysplastic syndrome and BD, and trisomy 8 was frequently seen, especially in intestinal BD. However, the association of BD with primary myelofibrosis (PMF) has not been well documented. A 58-year-old Japanese female was diagnosed with PMF in 2014. The symptoms of PMF resolved with ruxolitinib. However, she developed fever and intestinal perforation due to multiple ulcers in the terminal ileum in 2017. Intestinal perforation recurred 1 month later, and the dose of ruxolitinib was tapered. After discontinuation of ruxolitinib, she presented with recurrent oral aphthous ulcers and uveitis. Subsequently, intestinal perforation recurred, and she was diagnosed with intestinal BD. Trisomy 8 was identified in her peripheral blood. She underwent steroid therapy, azathioprine, and infliximab. This case suggests relationships between PMF, trisomy 8, and BD.
- Reversine exhibits antineoplastic activity in JAK2V617F-positive myeloproliferative neoplasms. [Journal Article]
- SRSci Rep 2019 Jul 09; 9(1):9895
- JAK2/STAT signaling participates in the Ph-negative myeloproliferative neoplasms (MPN) pathophysiology and has been targeted by ruxolitinib, a JAK1/2 inhibitor. In the present study, the impact of ru…
JAK2/STAT signaling participates in the Ph-negative myeloproliferative neoplasms (MPN) pathophysiology and has been targeted by ruxolitinib, a JAK1/2 inhibitor. In the present study, the impact of ruxolitinib treatment on cytoskeleton-related genes expression was explored. In SET2 cells, AURKA and AURKB expression/activity were downregulated in a dose- and time-dependent manner by ruxolitinib. Reversine, a multikinase inhibitor selective for aurora kinases, reduced cell viability in a dose- and/or time-dependent manner in JAK2V617F cells. Reversine significantly increased apoptosis and mitotic catastrophe, and reduced cell proliferation and clonogenic capacity in SET2 and HEL cells. In the molecular scenario, reversine induced DNA damage and apoptosis markers, as well as, reduced AURKA and AURKB expression/activity. In SET2 cells, reversine modulated the expression of 32 out of 84 apoptosis-related genes investigated, including downregulation of antiapoptotic (BCL2, BCL2L1, and BIRC5) and upregulation of proapoptotic (BIK, BINP3, and BNIP3L) genes. Synergism experiments indicated that low dose of reversine had a potentiating effect under ruxolitinib treatment at low doses in SET2 cells. In summary, our exploratory study establishes new targets, related to the regulation of the cellular cytoskeleton, for potential pharmacological intervention in MPN. These findings indicate that AURKA and AURKB participate in the JAK2/STAT signaling pathway and contribute to the MPN phenotype.
- Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2V617F cells. [Journal Article]
- INInvest New Drugs 2019 Jul 08
- JAK2V617F can mimic growth factor signaling, leading to PI3K/AKT/mTOR activation and inhibition of autophagy. We hypothesized that selective inhibition of JAK1/2 by ruxolitinib could induce autophagy…
JAK2V617F can mimic growth factor signaling, leading to PI3K/AKT/mTOR activation and inhibition of autophagy. We hypothesized that selective inhibition of JAK1/2 by ruxolitinib could induce autophagy and limit drug efficacy in myeloproliferative neoplasms (MPN). Therefore, we investigated the effects of ruxolitinib treatment on autophagy-related genes and cellular processes, to determine the potential benefit of autophagy inhibitors plus ruxolitinib in JAK2V617F cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2V617F cells, ruxolitinib treatment induced autophagy and modulated 26 out of 79 autophagy-related genes. Ruxolitinib treatment reduced the expressions of important autophagy regulators, including mTOR/p70S6K/4EBP1 and the STAT/BCL2 axis, in a dose- and time-dependent manner. Pharmacological inhibition of autophagy was able to significantly suppress ruxolitinib-induced autophagy and increased ruxolitinib-induced apoptosis. Mutations in autophagy-related genes were found in 15.5% of MPN patients and were associated with increased age and a trend towards worse survival. In conclusion, ruxolitinib induces autophagy in JAK2V617F cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2V617F-mutated MPNs.
- [Clinical application of gene mutation information in myeloproliferative neoplasms]. [Journal Article]
- RKRinsho Ketsueki 2019; 60(6):610-618
- Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, characterized by constitutive acti…
Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, characterized by constitutive activation of JAK/STAT signaling. JAK2, MPL, and CALR mutations are considered "driver mutations" and are directly implicated in the disease pathogenesis by activation of JAK2/STAT signaling. In addition to these driver mutations, several other mutations in epigenome regulatory and RNA splicing molecules have been found. This genetic information, especially regarding driver mutations, is essential for the diagnosis of MPN. Furthermore, assessment of non-driver mutations is also becoming increasingly important for disease risk assessment and treatment strategy definition.
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- Overview of the Mutational Landscape in Primary Myelofibrosis and Advances in Novel Therapeutics. [Journal Article]
- APAsian Pac J Cancer Prev 2019 06 01; 20(6):1691-1699
- Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematological presentations, including thrombosis, bleeding diathesis and marrow fibrosis. It is estimated to…
Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematological presentations, including thrombosis, bleeding diathesis and marrow fibrosis. It is estimated to have an incidence of 1.5 per 100,000 people each year. Although JAK2 or MPL mutations are seen in PMF, several other mutations have recently been documented, including mutations in CALR, epigenetic regulators like TET, ASXL1, and 13q deletions. The identification of these mutations has improved the ability to develop novel treatment options. These include JAK inhibitors like ruxolitinib, heat shock protein-90 inhibitors like ganetespib, histone deacetylase inhibitors including panobinostat, pracinostat, vorinostat and givinostat, hypomethylating agents like decitabine, hedgehog inhibitors like glasdegib, PI3K, AKT and mTOR inhibitors like everolimus as well as telomerase inhibitors like imtelstat. Research on novel therapeutic options is being actively pursued in order to expand treatment options for primary myelofibrosis however currently, there is no curative therapy other than allogenic hematopoietic stem cell transplantation (ASCT) which is possible in select patients.