New targeted therapies for relapsed pediatric acute lymphoblastic leukemia

Pierro, Joanna; Hogan, Laura; Bhatla, Teena; Carroll, William L.

doi:10.1080/14737140.2017.1347507

Cited by 37 publications

(34 citation statements)

References 93 publications

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“…Chimeric antigen receptor (CAR) T cells represent a new potential option for relapsed patients with B-ALL, but even for this new and promising genre of treatment, escape mechanisms are common 36 . For relapsed patients with T-ALL, the options are even more limited 37 . Chemoresistance, particularly to GC, is usually a prime characteristic of relapse 1 , 3 , 38 .…”

Section: Discussionmentioning

confidence: 99%

Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death

et al. 2018

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Synthetic glucocorticoids (GCs) are used to treat lymphoid cancers, but many patients develop resistance to treatment, especially to GC. By identifying genes that influence sensitivity to GC-induced cell death, we found that histone methyltransferases G9a and G9a-like protein (GLP), two glucocorticoid receptor (GR) coactivators, are required for GC-induced cell death in acute lymphoblastic leukemia (B-ALL) cell line Nalm6. We previously established in a few selected genes that automethylated G9a and GLP recruit heterochromatin protein 1γ (HP1γ) as another required coactivator. Here, we used a genome-wide analysis to show that HP1γ is selectively required for GC-regulated expression of the great majority of GR target genes that require G9a and GLP. To further address the importance of G9a and GLP methylation in this process and in cell physiology, we found that JIB-04, a selective JmjC family lysine demethylase inhibitor, increased G9a methylation and thereby increased G9a binding to HP1γ. This led to increased expression of GR target genes regulated by G9a, GLP and HP1γ and enhanced Nalm6 cell death. Finally, the KDM4 lysine demethylase subfamily demethylates G9a in vitro, in contrast to other KDM enzymes tested. Thus, inhibiting G9a/GLP demethylation potentially represents a novel method to restore sensitivity of treatment-resistant B-ALL tumors to GC-induced cell death.

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Section: Discussionmentioning

confidence: 99%

Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death

et al. 2018

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“…However, the management of relapsed and refractory ALL is still difficult due to chemoresistance. Despite efforts to intensify re-induction strategies, including allogenic hematopoietic stem cell transplantation, the Overall survival (OS) rates for patients with relapsed ALL remain between 25 and 40%, highlighting the need for researches on new promising drugs, such as immunotherapeutic agents [19]. However, the mechanisms underlying ALL progression, relapse and resistance remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a novel childhood acute lymphoblastic leukemia cell line, HXEX-ALL1, with chromosome 9p and 17p deletions

et al. 2019

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Background Although contemporary chemotherapy has improved the cure rate of childhood acute lymphoblastic leukemia (ALL) to nearly 90%, relapsed/refractory ALL is still a leading cause of tumor-related death in children. To clarify the underlying mechanisms of relapsed/refractory childhood ALL, researchers urgently need to establish novel cell models from patients with relapsed ALL after treatment with contemporary chemotherapy. Methods Cell culture technique was used to establish the HXEX-ALL1 cell line from primary B cell precursor ALL (BCP-ALL) cells. Molecular and cellular biological techniques including flow cytometry, polymerase chain reaction (PCR), short tandem repeat (STR) analysis, conventional cytogenetics, and chromosomal microarray analysis (CMA) were used to characterize the HXEX-ALL1 cell line. Nude mice were used for xenograft studies. Results A stable ALL cell line, HXEX-ALL1, derived from a 6-year-old boy of Han nationality with BCP-ALL at the second relapse, was established and maintained in culture for more than 18 months. The HXEX-ALL1 cell line was authenticated as being derived from primary leukemia cells based on morphologic, immunophenotypic, cytogenetic and STR analyses and demonstrated tumorigenicity in nude mice. WGS data showed that there were 27,006 novel single nucleotide polymorphisms (SNPs) and 193,951 novel insertion/deletions (InDels) in HXEX-ALL1 cells. Compared with the other BCP-ALL cell lines in use, the HXEX-ALL1 cells have a special karyotype represented by trisomy 8 and 9p and 17p deletions with a multidrug resistance phenotype, especially highly resistant to asparaginase. Conclusions The HXEX-ALL1 cell line may prove to be a useful model for the study of relapsed/refractory childhood ALL, particularly for the researches on asparaginase resistance.

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“…A kezelésre reagáló betegek residualis tumorsejtjeinek biológiai viselkedése előre jelezheti a későbbi relapsusokat. A legtöbb esetben (több mint 90%-ban) a recidívát okozó klón minor szubklón formájában már a diagnózis idején nyert biológiai mintákban jelen van, és terápia-rezisztencia vagy klonális evolúció révén jut szelekciós előnyhöz [5].…”

Section: New and Traditional Directions In The Biology And Managementunclassified

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

et al. 2018

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Az utóbbi néhány évtized klinikai előrelépéseinek köszönhetően az akut lymphoblastos leukaemiás (ALL-) gyermekek nagy hányada ma az első vonalbeli kemoterápiás protokollok révén meggyógyul, és küzd a kortársak közé való visszatérés problémáival. Azonban a betegek jelentős részénél súlyos akut és késői terápiás mellékhatásokkal kell szá-molni. Emellett egyes betegcsoportok (például MLL-átrendeződéssel, hipodiploiditással, IKZF1-mutációval vagy korai prekurzor T-sejtes fenotípussal jellemezhető betegek) túlélése messze elmarad az átlagostól. Számukra nyújta-nak jobb klinikai kilátásokat az újabb betegellátási stratégiák: komplex géndiagnosztika, molekulárisan célzott daganatgátlás, immunonkológia és sejtterápia. Harminc feletti azon géneknek a száma, amelyek eltéréseit azonosították leukaemiás lymphoblastokban, és patobiológiai szerepük is valamennyire ismert. Ismerünk olyan betegcsoportot is (Philadelphia-like B-sejtes ALL), ahol a génexpressziós profilalkotás ad alapot a tirozin-kináz-inhibitorok használatá-nak. A leukaemiaasszociált immunfenotípus diagnóziskori áramlási citometriás meghatározásával és genetikai mód-szerekkel követhetővé vált a minimális residualis betegség. A blastfelszíni differenciációs klaszterek (elsősorban CD19, CD20 és CD22 a malignus B-sejteken) epitópjai monoklonális antitestekkel támadhatók. Fokozható a tumorellenes immunitás is, részben szintén a tumor sejtfelszíni markereinek (bispecifikus T-sejt-kapcsolóknál, kiméra antigénrecep-torú T-sejtes terápiánál), részben pedig a tumorspecifikus immunsejteknek (immunellenőrzőpont-gátlóknál) a kihasználása révén. A jelen közleményben áttekintést kívánunk adni a patogenetika új irányairól, a betegségkövetés modern módjairól és a célzott citotoxicitás innovatív lehetőségeiről biztató klinikai tanulmányok alapján. Orv Hetil. 2018; 159(20): 786-797. Keywords: akut lymphoblastos leukaemia, patogenezis, toxicitás, immunterápia, célzott molekuláris terápia New and traditional directions in the biology and management of childhood acute lymphoblastic leukemiaOwing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them: complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy. The number of genes with identified alterations in leukemic lymphoblasts is over thirty and their pathobiologic role is only partly clear. There are known patient groups where the use of specific drugs is based on gene expression profiling (e.g., tyrosine kinase inhibitors in Philadelphia-like B-cell ALL). The continuous assessment of min...

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New targeted therapies for relapsed pediatric acute lymphoblastic leukemia

Cited by 37 publications

References 93 publications

Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death

Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death

Establishment and characterization of a novel childhood acute lymphoblastic leukemia cell line, HXEX-ALL1, with chromosome 9p and 17p deletions

Új és hagyományos irányok a gyermekkori akut lymphoblastos leukaemia biológiájában és ellátásában

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