Publications by authors named "Chunxu Qu"

Article Synopsis
  • Despite high cure rates for childhood acute lymphoblastic leukemia (ALL), it remains a major cause of cancer-related deaths in children, especially among those initially classified as standard-risk (SR).
  • Researchers analyzed genomic data from over 1,300 children with ALL to identify factors influencing relapse, focusing on comparing patients who relapsed against those who stayed in remission for five years.
  • Findings indicated that specific genomic subtypes and chromosomal alterations significantly affect relapse risk, highlighting the need for detailed genetic analysis to improve risk assessment and treatment strategies in childhood ALL.
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Article Synopsis
  • Acute lymphoblastic leukemia (γδ T-ALL) is a rare and complex condition in children, prompting a study of 200 pediatric cases to identify its clinical and genetic characteristics.
  • The research revealed that very young children (under 3 years) with γδ T-ALL face a significantly high risk and display specific genetic changes, particularly involving STAG2 inactivation and LMO2 activation.
  • Importantly, their findings suggest that targeting DNA repair pathways linked to STAG2 inactivation with specific drugs could offer new treatment options and help classify patients based on their risk levels.
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  • * The study found that 11% of patients who relapsed after InO developed mutations in the CD22 gene, which allowed cancer cells to evade treatment, often through losing or altering the CD22 protein's structure.
  • * Additional mutations were also seen in genes related to DNA damage response, raising concerns about how cancer cells adapt post-treatment, emphasizing the need for understanding these mechanisms to improve future therapies, especially before procedures like stem cell transplantation.
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Article Synopsis
  • Inotuzumab ozogamicin (InO) is a targeted therapy for B-cell acute lymphoblastic leukemia that delivers a cytotoxic drug to cells expressing the CD22 antigen.
  • A study on patients treated with InO revealed that approximately 11% exhibited genomic mutations contributing to treatment resistance, with various escape mechanisms like protein truncation and destabilization.
  • The findings highlight the role of DNA damage repair processes in promoting CD22 mutations and suggest that understanding these genetic changes can help improve treatment strategies for overcoming resistance to therapy.
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Sequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs.

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Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.

Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing.

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The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/β-catenin-mediated EMT-like program.

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The article proposes the use of a semi-rigid energy-dissipation connection combined with a U-shaped metal damper to avoid brittle failure of rigid steel beam-column connections under seismic loading. The U-shaped metal damper connects the H-section column and the H-section beam to form a new energy-dissipation connection as an energy-dissipation member. Compared with the existing research, this connection has a stable energy-dissipation performance and great ductility.

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Article Synopsis
  • Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and a study of 2,754 patients reveals that despite a low mutation burden, each case typically has about four important genetic alterations.
  • Researchers identified 376 potential driver genes linked to various functions like gene regulation and cell processes, with many patients having unique gene changes associated with leukemia.
  • The study highlights a difference in mutation patterns between B-ALL subtypes, with certain genetic alterations having significant implications for prognosis and potential treatment strategies.
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Rare diseases (RDs) are naturally associated with a low prevalence rate, which raises a big challenge due to there being less data available for supporting preclinical and clinical studies. There has been a vast improvement in our understanding of RD, largely owing to advanced big data analytic approaches in genetics/genomics. Consequently, a large volume of RD-related publications has been accumulated in recent years, which offers opportunities to utilize these publications for accessing the full spectrum of the scientific research and supporting further investigation in RD.

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Article Synopsis
  • DNA methylation plays a key role in cell development and stability, but cancer often disrupts this process, showing a global loss of methylation and increased CpG island hypermethylation.
  • Acute lymphoblastic leukemia (ALL), the most common childhood cancer, presents unique methylation patterns, revealing hypermethylation of CpG islands without the typical global loss seen in other cancers.
  • Whole-genome analysis indicates significant variability in CpG island hypermethylation among ALL patients, influenced by specific genes (TET2 and DNMT3B), highlighting a distinct regulatory mechanism for methylation in leukemia.
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Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is characterized by clonal expansion of natural killer (NK) cells where the underlying genetic mechanisms are incompletely understood. In the present study, we report somatic mutations in the chemokine gene CCL22 as the hallmark of a distinct subset of CLPD-NK. CCL22 mutations were enriched at highly conserved residues, mutually exclusive of STAT3 mutations and associated with gene expression programs that resembled normal CD16/CD56 NK cells.

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Unlabelled: ZNF384-rearranged fusion oncoproteins (FO) define a subset of lineage ambiguous leukemias, but their mechanistic role in leukemogenesis and lineage ambiguity is poorly understood. Using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPC) and a Ep300::Znf384 knockin mouse model, we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal. In mouse HSPCs, concomitant lesions, such as NRASG12D, were required for fully penetrant leukemia, whereas in human HSPCs, expression of ZNF384 FO drove B/myeloid leukemia, with sensitivity of a ZNF384-rearranged xenograft to FLT3 inhibition in vivo.

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Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL.

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Unlabelled: NUP98 fusion oncoproteins (FO) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains.

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Immunotherapies directed against B-cell surface markers have been a common developmental strategy to treat B-cell malignancies. The immunoglobulin heavy chain surrogate light chain (SLC), comprising the VpreB1 (CD179a) and Lamda5 (CD179b) subunits, is expressed on pro- and pre-B cells, where it governs pre-B-cell receptor (BCR)-mediated autonomous survival signaling. We hypothesized that the pre-BCR might merit the development of targeted immunotherapies to decouple "autonomous" signaling in B-lineage acute lymphoblastic leukemia (B-ALL).

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We evaluate clinical significance of recently identified subtypes of acute lymphoblastic leukemia (ALL) in 598 children treated with minimal residual disease (MRD)-directed therapy. Among the 16 B-ALL and 8 T-ALL subtypes identified by next generation sequencing, , high-hyperdiploid and -rearranged B-ALL had the best five-year event-free survival rates (95% to 98.4%); , PAX5alt, T-cell, ETP, iAMP21, and hypodiploid ALL intermediate rates (80.

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CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs.

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Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to .

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Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years).

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Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-X/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-X without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment.

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Acute erythroid leukemia (AEL) is characterized by a distinct morphology, mutational spectrum, lack of preclinical models, and poor prognosis. Here, using multiplexed genome editing of mouse hematopoietic stem and progenitor cells and transplant assays, we developed preclinical models of AEL and non-erythroid acute leukemia and describe the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1, and Nfix resulted in the development of leukemia with an erythroid phenotype, accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis.

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Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16).

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