Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease

Human Resource Flexibility as a Mediating Variable Between High Performance Work Systems and Performance

Much of the human resource management literature has demonstrated the impact of high performance work systems (HPWS) on organizational performance. A new generation of studies is emerging in this literature that recommends the inclusion of mediating variables between HPWS and organizational performance. The increasing rate of dynamism in competitive environments suggests that measures of employee adaptability should be included as a mechanism that may explain the relevance of HPWS to firm competitiveness. On a sample of 226 Spanish firms, the study’s results confirm that HPWS influences performance through its impact on the firm’s human resource (HR) flexibility

The Akt Forkhead Box O Transcription Factor Axis Regulates Human Cytomegalovirus Replication

The protein kinase Akt broadly impacts many cellular processes, including mRNA translation, metabolism, apoptosis, and stress responses. Inhibition of phosphatidylinositol 3-kinase (PI3K), a lipid kinase pivotal to Akt activation, triggers various herpesviruses to reactivate from latency. Hence, decreased Akt activity may promote lytic replication. Here, we show that Akt accumulates in an inactive form during human cytomegalovirus (HCMV) infection of permissive fibroblasts, as indicated by hypophosphorylation of sites that activate Akt, decreased phosphorylation of PRAS40, and pronounced nuclear localization of FoxO3a, a substrate that remains cytoplasmic when Akt is active. HCMV strongly activates mTORC1 during lytic infection, suggesting a potential mechanism for Akt inactivation, since mTORC1 negatively regulates PI3K. However, we were surprised to observe that constitutive Akt activity, provided by expression of Akt fused to a myristoylation signal (myr-Akt), caused a 1-log decrease in viral replication, accompanied by defects in viral DNA synthesis and late gene expression. These results indicated that Akt inactivation is required for efficient viral replication, prompting us to address which Akt substrates underpin this requirement. Interestingly, we found that short interfering RNA knockdown of FoxO3a, but not FoxO1, phenocopied the defects caused by myr-Akt, corroborating a role for FoxO3a. Accordingly, a chimeric FoxO3a-estrogen receptor fusion protein, in which nuclear localization is regulated by 4-hydroxytamoxifen instead of Akt, reversed the replication defects caused by myr-Akt. Collectively, our results reveal a role for FoxO transcription factors in HCMV lytic replication and argue that this single class of Akt substrates underpins the requirement for Akt inactivation during productive infection. IMPORTANCE Evidence from diverse herpesvirus infection models suggests that the PI3K/Akt signaling pathway suppresses reactivation from latency and that inactivation of the pathway stimulates viral lytic replication. Here, we show that Akt accumulates in an inactive state during HCMV infection of lytically permissive cells while the presence of constitutive Akt activity causes substantial viral replication defects. Although Akt phosphorylates a diverse array of cellular substrates, we identify an important role for the Forkhead box class O transcription factors. Our findings show that when FoxO3a nuclear localization is decoupled from its negative regulation by Akt, the viral replication defects observed in the presence of constitutively active Akt are reversed. Collectively, our results reveal that HCMV inactivates Akt to promote the nuclear localization of FoxO transcription factors, which strongly implies that FoxOs play critical roles in transactivating cellular and/or viral genes during infection. Copyright © 2022 Zhang et al.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial

Contains fulltext : 138929.pdf (publisher's version ) (Open Access)The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25.1, 55.6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2.64, 95% CI 1.32, 5.31, p = 0.006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN45724312

Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse

INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies