Dysregulation of miR-125b Predicts Poor Response to Therapy in Pediatric Acute Lymphoblastic Leukemia

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3–independent growth in Ba/F3 cells and/or IL-9–independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

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Thioimidazoline based compounds reverse glucocorticoid resistance in human acute lymphoblastic leukemia xenografts

Organic & Biomolecular Chemistry ◽

10.1039/c5ob00779h ◽

2015 ◽

Vol 13 (22) ◽

pp. 6299-6312 ◽

Cited By ~ 6

Author(s):

Cara E. Toscan ◽

Marwa Rahimi ◽

Mohan Bhadbhade ◽

Russell Pickford ◽

Shelli R. McAlpine ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Poor Response ◽

Glucocorticoid Therapy ◽

Glucocorticoid Resistance ◽

Critical Component ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Human Acute Lymphoblastic Leukemia

Glucocorticoids form a critical component of chemotherapy regimens for pediatric acute lymphoblastic leukemia and initial poor response to glucocorticoid therapy is predictive of inferior outcome.

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Multi-omics molecular phenotyping of childhood acute lymphoblastic leukemia cell lines reveals novel drug vulnerabilities

10.21203/rs.3.rs-443839/v1 ◽

2021 ◽

Author(s):

Matthias Stahl ◽

Luay Aswad ◽

Isabelle Leo ◽

Elena Kunold ◽

Frederik Post ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Cell Lines ◽

Drug Sensitivity ◽

Lymphoblastic Leukemia ◽

Leukemia Cell ◽

Poor Response ◽

Response To Therapy ◽

Proteomics Data ◽

Bryostatin 1 ◽

Childhood All

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although standard-of-care chemotherapeutics are sufficient for most ALL cases, there are subsets of patients with poor response who relapse in disease. The biology underlying differences between subtypes and their response to therapy has only partially been explained by genetic and transcriptomic profiling. To characterize ALL subtypes and identify novel pharmacologic vulnerabilities, we performed comprehensive multi-omic analyses of 49 widely-used childhood ALL cell lines, using proteomics, transcriptomics, and pharmacoproteomic characterization. This enabled us to characterize the functional impact of genetic fusions and cellular differentiation states. The proteomics data revealed differences in spliceosome and p53 levels not evident in the transcriptomics data and with improved correlation to drug sensitivity. Focusing on BCP-ALL cell lines, we connected the genotype, molecular phenotype, and functional phenotype with drug response data on 528 oncology drugs. Here, we identified the DAG-analog Bryostatin-1 as a novel therapeutic candidate in the MEF2D-HNRNPUL1 fusion high-risk subtype, for which this drug activated pro-apoptotic ERK signaling associated with molecular mediators of pre-B cell negative selection. Our data also forms an interactive online resource with navigable proteomics, transcriptomics, and drug sensitivity profiles at https://lehtio-lab.se/forall/.

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Faculty Opinions recommendation of Epigenetics in pediatric acute lymphoblastic leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.731120594.793548064 ◽

2018 ◽

Author(s):

Kenneth Ramos

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Pediatric Acute Lymphoblastic Leukemia

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Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

Scientific Reports ◽

10.1038/s41598-021-95109-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shumaila Sayyab ◽

Anders Lundmark ◽

Malin Larsson ◽

Markus Ringnér ◽

Sara Nystedt ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Large Scale ◽

Somatic Mutations ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Point Mutations ◽

Driver Genes ◽

Protein Coding ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

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Pediatric acute lymphoblastic leukemia complicated by secondary hemophagocytic lymphohistiocytosis

Pediatric Blood & Cancer ◽

10.1002/pbc.22064 ◽

2009 ◽

Vol 53 (3) ◽

pp. 491-492 ◽

Cited By ~ 14

Author(s):

Omer Devecioglu ◽

Sema Anak ◽

Didem Atay ◽

Pinar Aktan ◽

Esra Devecioglu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hemophagocytic Lymphohistiocytosis ◽

Lymphoblastic Leukemia ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Secondary Hemophagocytic Lymphohistiocytosis

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Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

Journal of Clinical Medicine ◽

10.3390/jcm10091926 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1926

Author(s):

Hiroto Inaba ◽

Ching-Hon Pui

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Detailed Analysis ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Treatment Strategies ◽

Chemotherapeutic Agents ◽

Response To Treatment ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Therapeutic Implications

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

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Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia

Genes ◽

10.3390/genes12020214 ◽

2021 ◽

Vol 12 (2) ◽

pp. 214

Author(s):

Željko Antić ◽

Stefan H. Lelieveld ◽

Cédric G. van der Ham ◽

Edwin Sonneveld ◽

Peter M. Hoogerbrugge ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Leukemic Cells ◽

Proliferative Potential ◽

Disease Evolution ◽

Pediatric Acute Lymphoblastic Leukemia ◽

First Relapse ◽

Mutational Processes

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes.

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