[A case of crizotinib-associated renal cysts].

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Deterministic reprogramming and signaling activation following targeted therapy in non-small cell lung cancer driven by mutations or oncogenic fusions.

INTRODUCTION: Targeted therapy is used to treat lung adenocarcinoma caused by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain and rare subtypes (<5%) of non-small cell lung cancer. These subtypes include fusion oncoproteins like anaplastic lymphoma kinase (ALK), ROS1, rearranged during transfection (RET), and other receptor tyrosine kinases (RTKs). The use of diverse selective oral inhibitors, including those targeting rat sarcoma viral oncogene homolog (KRAS) mutations, has significantly improved clinical responses, extending progression-free and overall survival. AREAS COVERED: Resistance remains a critical issue in lung adenocarcinoma, notably in EGFR mutant, echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion, and KRAS mutant tumors, often associated with epithelial-to-mesenchymal transition (EMT). EXPERT OPINION: Despite advancements in next generation EGFR inhibitors and EML4-ALK therapies with enhanced brain penetrance and identifying resistance mutations, overcoming resistance has not been abated. Various strategies are being explored to overcome this issue to achieve prolonged cancer remission and delay resistance. Targeting yes-associated protein (YAP) and the mechanisms associated with YAP activation through Hippo-dependent or independent pathways, is desirable. Additionally, the exploration of liquid-liquid phase separation in fusion oncoproteins forming condensates in the cytoplasm for oncogenic signaling is a promising field for the development of new treatments.

Individualized detection of TMPRSS2-ERG fusion status in prostate cancer: a rank-based qualitative transcriptome signature.

BACKGROUND: TMPRSS2-ERG (T2E) fusion is highly related to aggressive clinical features in prostate cancer (PC), which guides individual therapy. However, current fusion prediction tools lacked enough accuracy and biomarkers were unable to be applied to individuals across different platforms due to their quantitative nature. This study aims to identify a transcriptome signature to detect the T2E fusion status of PC at the individual level. METHODS: Based on 272 high-throughput mRNA expression profiles from the Sboner dataset, we developed a rank-based algorithm to identify a qualitative signature to detect T2E fusion in PC. The signature was validated in 1223 samples from three external datasets (Setlur, Clarissa, and TCGA). RESULTS: A signature, composed of five mRNAs coupled to ERG (five ERG-mRNA pairs, 5-ERG-mRPs), was developed to distinguish T2E fusion status in PC. 5-ERG-mRPs reached 84.56% accuracy in Sboner dataset, which was verified in Setlur dataset (n = 455, accuracy = 82.20%) and Clarissa dataset (n = 118, accuracy = 81.36%). Besides, for 495 samples from TCGA, two subtypes classified by 5-ERG-mRPs showed a higher level of significance in various T2E fusion features than subtypes obtained through current fusion prediction tools, such as STAR-Fusion. CONCLUSIONS: Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.

Gelling Bodies: Understanding the Mechanisms Underlying Arsenic Trioxide Action.

SUMMARY: The study by Bercier and colleagues investigates the mechanisms of action of arsenic trioxide (ATO). The authors find that ATO promotes transition of PML nuclear bodies to a gel-like state via the PML trimerization domain and a critical cysteine residue. Overall, this work sheds new light onto how PML-RARα, the oncogene of APL, is targeted by ATO for disease eradication. See related article by Bercier et al., p. 2548 (6).

Current landscape and future prospects of RET and ROS1 targets.

RET and ROS1 are becoming key targets for targeted therapy. To show current landscape of ROS1 and RET targets, a patent analysis was performed. The present results indicated that inhibitor structures of ROS1 target demonstrated unique elements compared with inhibitor structures of RET or BRAF targets. Our study was the first time to uncover that a number of inhibitor structures of ROS1 target contained sulfur and boron elements. The inhibitors of RET target could be developed for treatment of various cancers, including lung cancer, thyroid cancer, and other solid tumor, while the inhibitors of ROS1 target are virtually developed for treatment of lung cancer. Our findings provide a new insight for drug discovery of ROS1 and RET target.

Development of a Cell Line Containing the Chimeric ETV6-NTRK3 Gene. The Search for Mutations of the Tyrosine Kinase Chimeric Domain That Cause Resistance to Larotrectinib.

The development, registration, and further use of entrectinib and larotrectinib for the treatment of tumors resulting from oncogenic stimulation of chimeric neurotrophin receptors (TRK) attracted much interest to the mechanisms of tumor cells resistance to TRK inhibitors during treatment. In the presented study, a cell line carrying the chimeric gene ETV6-NTRK3 (HFF-EN) was created on the basis of human fibroblasts. The transcription level of the chimeric ETV6-NTRK3 gene in HFF-EN was comparable to the transcription level of the household ACTB gene, the expression of the ETV6-NTRKA protein was confirmed by immunoblotting. A comparison of the dose-effect curves of fibroblasts and HFF-EN cells showed a ~38-fold increase in the sensitivity of HFF-EN to larotrectinib. To obtain a cell model of the resistance to larotrectinib in NTRK-dependent cancer, we used cell passages with a gradually increasing concentration of larotrectinib and obtained six resistant clones. p.G623E c.1868G>A mutation was found in five clones, and p.R582W c.1744C>T mutation, previously not described as a resistance mutation, was found in one clone showing significantly less resistance. These results can be further used for more complete understanding of the mechanisms of the resistance to TRK inhibitors and for the development of new drugs.

Identification of MET fusions as novel therapeutic targets sensitive to MET inhibitors in lung cancer.

INTRODUCTION: Alterations in the MET gene, including amplifications and exon 14 skipping mutations, have been identified as actionable oncogenic alterations. However, MET fusions are rarely detected in lung cancer, and their sensitivity to therapeutics has not been systematically analyzed. METHODS: The data from 30876 lung cancer patients from the LAVA database and 7966 patients from cBioPortal database were screened. Basic demographic and clinical information for the patients harboring MET fusions were collected. A lung squamous cell cancer patient harboring a novel EML4-MET fusion was treated with crizotinib. Additionally, a literature review was performed to summarize the cases of patients harboring MET fusions and their treatment information. RESULTS: MET fusions were found in only 0.2% to 0.3% of lung cancer patients and appeared in almost all exons of the MET gene. Intragenic MET fusions were found in 52.6% (41/78) of the included patients. Crizotinib was effective for MET fusions, including a novel identified EML4-MET fusion, even after the failure of multiple lines of treatment. This result suggested that acquired MET fusions become more regionally selective, as they usually occurred in exons encoding the extracellular region. Interestingly, the MET-fused genes in primary MET fusions or acquired MET fusions were very different, which indicated the different functions and influences of the disease. CONCLUSION: MET fusions are rare, and half of the fusion types were intragenic fusions. Lung cancer patients harboring primary or acquired MET fusions could benefit from crizotinib. In addition, EML4-MET was first reported in this study as a novel MET fusion type.

A new approach used in docking study for predicting the combination drug efficacy in EML4-ALK target of NSCLC.

Combination drug treatments are usually used in many diseases, including cancers and AIDS. This treatment strategy is known as one of the cornerstone in therapies, which potentially reduces drug toxicity and drug resistance and also enhances therapeutic efficacy. Before using a drug in treatment, several experimental studies are done in vivo and in vitro to ensure the drug's efficacy. In such experimental studies, the drug's efficacy is evaluated with the help of drug dose ratio. In the combination drug experimental studies, the efficacy of the drugs is quantified with the Combination Index (CI) value and then interpreted by various terminologies like synergy, additive, and antagonism. Several computational models have now been invented for the speedy identification of combination drug efficacy. Unfortunately, none of these models have predicted the atomic level interaction of the combination drug with the target protein. This type of intermolecular interaction can be identified with the help of docking software. In the proposed work, we try to identify the intermolecular interaction and efficacy of the combination drug Crzizotinib and Temozolomide in the target of EML4-ALK in NSCLC by in silico study. The result of the study was evaluated with drug properties and Complex Energy (CE) of the docked complex rather than using docking score and binding energy. From this study, we could understand that first, Crizotinib and then after the Temozolomide drug binded on the EML4-ALK protein complex, showed very least CE and also identified that the combination of Crizotinib and Temozolomide drug are more effective in NSCLC.Communicated by Ramaswamy H. Sarma.

Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα.

The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates. In the current study, we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARα protein to explore a potential therapeutic approach for this variant APL. We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents. However, mild hyperthermia (42 °C) rapidly destabilized the ZBTB16/RARα fusion protein expressed in HeLa, 293T, and OCI-AML3 cells, followed by robust ubiquitination and proteasomal degradation. In contrast, hyperthermia did not affect the normal (i.e., unfused) ZBTB16 and RARα proteins, suggesting a specific thermal sensitivity of the ZBTB16/RARα fusion protein. Importantly, we found that the destabilization of ZBTB16/RARα was the initial step for oncogenic fusion protein degradation by hyperthermia, which could be blocked by deletion of nuclear receptor corepressor (NCoR) binding sites or knockdown of NCoRs. Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.

Targeting the Lysosomal Degradation of Rab22a-NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis.

Rab22a-NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a-NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52-mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63-linked ubiquitin chains on lysine112 of Rab22a-NeoF1, which is responsible for the binding of Rab22a-NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a-NeoF1. PINK1 is able to phosphorylate Rab22a-NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a-NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a-NeoF1. These findings reveal that the lysosomal degradation of Rab22a-NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A-NeoF1 fusion gene.

Partial response to pralsetinib in an advanced pulmonary sarcomatoid carcinoma patient harboring a KIF5B-RET rearrangement: a case report.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare and unconventional non-small-cell lung cancer (NSCLC) that appears to be aggressive, with a poor prognosis and response to conventional treatment. Approximately 30% of PSCs have potentially targetable genomic alterations, but few studies have involved RET gene fusions, and corresponding targeted therapies are lacking. CASE PRESENTATION: In this report, we describe a patient with PSC harboring a KIF5B-RET gene fusion who was initially diagnosed with stage IVb lung cancer. Due to the poor performance status, the patient was unable to tolerate any radiotherapy or chemotherapy. Based on the next-generation sequencing (NGS) result of RET gene fusion, the patient was treated with pralsetinib. Two months after the treatment, the patient achieved a partial response. CONCLUSIONS: Our case indicates that RET is one of the main driver oncogenes of PSC and provides useful information for precise RET inhibitor administration in the future. Thus, the use of comprehensive genomic profiling may provide important treatment options for PSC.

Liquid biopsy for the detection of resistance mutations to ROS1 and RET inhibitors in non-small lung cancers: A case series study.

Liquid biopsy can identify gene alterations that are associated with resistance to fusion gene-targeted treatments. In this study, we present three cases of advanced non-small cell lung cancer (NSCLC) harboring gene fusions; cell-free DNA (cfDNA) was used to assess the resistance mutations. A patient with MET amplification underwent RET-fusion NSCLC treatment with selpercatinib. A patient with ROS1 G2032R underwent ROS1-fusion NSCLC treatment with crizotinib. A patient who underwent ROS1-fusion NSCLC treatment with crizotinib harbored no somatic mutations. This case series shows that cfDNA analysis can identify potentially actionable genomic alterations, after disease progression, in targeted therapy for fusion genes. TRIAL REGISTRATION: The study was registered in the UMIN Clinical Trial Registry (UMIN 000017581).

Detection of an EML4-ALK fusion mutation secondary to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer: a case report.

BACKGROUND: For epidermal growth factor receptor-mutant (EGFR-mutant) advanced non-small cell lung cancer (NSCLC) patients, EGFR-tyrosine inhibitors such as gefitinib, erlotinib, and osimertinib, are recommended as the preferred first-line treatment. Unfortunately, relevant drug resistance is often inevitable and for first and second generation EGFR-tyrosine kinase inhibitors (TKIs), drug resistance most commonly (50-60% of cases) occurs at the secondary point mutation T790M. Second-line treatments may include administering the third generation of EGFR-TKIs, such as osimertinib and almonertinib. In a few relevant studies, rearrangement of the anaplastic lymphoma kinase (ALK) gene was detected in patients with T790M mutation after drug resistance to osimertinib re-occurred following administration as a second-line treatment. The studies concluded that ALK rearrangement is a rare but critical drug resistance mechanism for osimertinib. However, to date, it remains unclear whether almonertinib also triggers the same ALK rearrangement. The current case study is the first one detailing the detection of an ALK rearrangement after almonertinib resistance in advanced EGFR-mutant NSCLC, which contributes to the limited body of literature examining ALK rearrangement as a mechanism of resistance to EGFR-TKIs in advanced EGFR-mutant NSCLC. CASE DESCRIPTION: Herein, we present a 35-year-old female patient with EGFR-mutant advanced NSCLC in the last trimester of pregnancy. The patient was administered multiple treatments, including first-line icotinib and second-line almonertinib. According to the next-generation sequencing (NGS) assay after almonertinib resistance, the development of an EML4-ALK fusion mutation was considered to be a potential mechanism of almonertinib resistance. Subsequently, the patient received a combination of almonertinib and crizotinib, and at the last follow-up, the treatment showed a curative effect and then maintained a one-month stable disease. CONCLUSIONS: This case report suggests that ALK rearrangement may be a potential mechanism of almonertinib resistance. The combination of ALK TKI therapy and EGFR TKI may be a viable strategy for almonertinib-resistant NSCLC patients induced by ALK rearrangement.

Detection of ALK fusion variants by RNA-based NGS and clinical outcome correlation in NSCLC patients treated with ALK-TKI sequences.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. METHODS: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. RESULTS: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. CONCLUSION: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes.

MicroRNA-125b Accelerates and Promotes PML-RARa-driven Murine Acute Promyelocytic Leukemia.

Objective: Most acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood. Methods: Based on the frequent overexpression of miR-125-family miRNAs in acute promyelocytic leukemia, we examined the consequence of this phenomenon by using an inducible mouse model overexpressing human miR-125b. Results: MiR-125b expression significantly accelerates PML-RARa-induced leukemogenesis, with the resultant induced leukemia being partially dependent on continued miR-125b overexpression. Interestingly, miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio, confirming the clinical observation in acute promyelocytic leukemia patients. Conclusion: This study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia, indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.

PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα.

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (As2O3) or/and all-trans retinoic acid. The protein arginine methyltransferase 5 (PRMT5) is involved in tumorigenesis. However, little is known about the biological function and therapeutic potential of PRMT5 in APL. Here, we show that PRMT5 is highly expressed in APL patients. PRMT5 promotes APL by interacting with PML-RARα and suppressing its ubiquitination and degradation. Mechanistically, PRMT5 attenuates the interaction between PML-RARα and its ubiquitin E3 ligase RNF4 by methylating RNF4 at Arg164. Notably, As2O3 treatment triggers the dissociation of PRMT5 from PML nuclear bodies, attenuating RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Moreover, knockdown of PRMT5 and pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 significantly inhibit APL cells growth. The combination of EPZ015666 with As2O3 shows synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with As2O3, might be a promising therapeutic strategy against APL.

Reliability analysis of exonic-breakpoint fusions identified by DNA sequencing for predicting the efficacy of targeted therapy in non-small cell lung cancer.

BACKGROUND: Diverse genomic breakpoints of fusions that localize to intronic, exonic, or intergenic regions have been identified by DNA next-generation sequencing (NGS), but the role of exonic breakpoints remains elusive. We investigated whether exonic-breakpoint fusions could predict matched targeted therapy efficacy in non-small cell lung cancer (NSCLC). METHODS: NSCLC samples were analyzed by DNA NGS, RNA NGS, immunohistochemistry (IHC), and fluorescence in situ hybridization. RESULTS: Using DNA NGS, kinase fusions were identified in 685 of 7148 (9.6%) NSCLCs, with 74 harboring exonic-breakpoint fusions, mostly anaplastic lymphoma kinase (ALK) fusions. RNA NGS and IHC revealed that 11 of 55 (20%) exonic-breakpoint fusions generated no aberrant transcript/protein, possibly due to open reading frame disruption or different gene transcriptional orientations. Four cases of genomic-positive but RNA/protein-negative fusions were treated with matched targeted therapy, but progressive disease developed within 2 months. Nevertheless, 44 of 55 (80%) exonic-breakpoint fusions produced chimeric transcripts/proteins, possibly owing to various alternative splicing patterns, including exon skipping, alternative splice site selection, and intron retention. Most of these genomic- and RNA/protein-positive fusion cases showed a clinical response to matched targeted therapy. Particularly, there were no differences in objective response rate (P = 0.714) or median progression-free survival (P = 0.500) between intronic-breakpoint (n = 56) and exonic-breakpoint ALK fusion subtypes (n = 11) among ALK RNA/protein-validated patients who received first-line crizotinib. CONCLUSIONS: Exonic-breakpoint fusions may generate in-frame fusion transcripts/proteins or not, and thus are unreliable for predicting the efficacy of targeted therapy, which highlights the necessity of implementing RNA or protein assays for functional validation in exonic-breakpoint fusion cases.

Diagnosis and management of TRK fusion cancer.

The tropomyosin receptor kinase (TRK) family of proteins is encoded by neurotrophic tyrosine receptor kinase (NTRK) genes and has a role in the development and normal functioning of the nervous system. NTRK gene fusions have been identified as oncogenic drivers in a wide range of tumors in both adult and pediatric patients. There has recently been a paradigm shift in cancer treatment toward biomarker-based targeted therapies, as an increasing number of actionable targets are being identified across different tumors and/or tumor histologies. These targeted agents offer greater comparative effectiveness and safety vs historical nontargeted standard therapies. The development of drugs that specifically target oncogenic drivers of cancer has led to the emergence of screening technologies to identify the patients most likely to benefit from targeted therapy. This review describes the role of NTRK gene fusions in cancer and outlines the epidemiology of NTRK gene fusions, the therapeutic benefits of targeting TRK fusions with small molecule inhibitors, and recommendations for NTRK gene fusion testing in adult and pediatric patients with cancer, in order to guide treatment decisions.

EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene occurs in approximately 5% of non-small-cell lung cancers (NSCLCs). The development of ALK tyrosine kinase inhibitors (ALK-TKIs) is a major advance in treating NSCLC with the ALK fusion gene. Nevertheless, acquired resistance to ALK-TKIs ultimately limits their use. A prevalent mechanism of drug resistance in kinases occurs through the mutation of G1202R in ALK. However, the mechanisms underlying G1202R resistance to ceritinib are not fully understood. Here, we demonstrated that the expression of EML4-ALK G1202R mutation in A549 cells induced an epithelial-mesenchymal transition (EMT) phenotype and significantly increased the migration and invasion abilities. These phenomena may be due to the upregulation of signal transducer and activator of transcription 3 (STAT3), accompanied by the elevated expression of Slug in EML4-ALK G1202R mutant cells. Furthermore, the combination of ALK and STAT3 inhibitors restored the sensitivity of EML4-ALK G1202R mutant cells to ceritinib. In conclusion, these data indicate that the EML4-ALK G1202R mutation mediates the EMT phenotype by activating the STAT3/Slug signaling pathway, resulting in resistance to ceritinib, and that the combination of STAT3 and ALK inhibitors may overcome ALK mutation-driven drug resistance in the clinic.

MicroRNA-125b Accelerates and Promotes PML-RARa-driven Murine Acute Promyelocytic Leukemia / 生物医学与环境科学（英文）

Objective@#Most acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood.@*Methods@#Based on the frequent overexpression of miR-125-family miRNAs in acute promyelocytic leukemia, we examined the consequence of this phenomenon by using an inducible mouse model overexpressing human miR-125b.@*Results@#MiR-125b expression significantly accelerates PML-RARa-induced leukemogenesis, with the resultant induced leukemia being partially dependent on continued miR-125b overexpression. Interestingly, miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio, confirming the clinical observation in acute promyelocytic leukemia patients.@*Conclusion@#This study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia, indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.