Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

Scheijen, Blanca; Boer, Judith M.; Marke, René; Tijchon, Esther; Schenau, Dorette van Ingen; Waanders, Esmé; Emst, Liesbeth van; Meer, Laurens T. van der; Pieters, Rob; Escherich, Gabriele; Horstmann, Martin; Sonneveld, Edwin; Venn, Nicola C.; Sutton, Rosemary; Dalla‐Pozza, Luciano; Kuiper, Roland P.; Hoogerbrugge, Peter M.; Boer, Monique L. den; Leeuwen, Frank N. van

doi:10.3324/haematol.2016.153023

Cited by 50 publications

(47 citation statements)

References 46 publications

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“…Despite generally favorable outcomes of childhood ALL, relapse still occurs with a dismal prognosis, thus it is important to develop novel therapeutic modalities. Drug resistance and early disease recurrence lead to limited survival of patients with ALL (13). Previous attempts to overcome drug resistance by increasing the dose of chemotherapeutic agents have resulted in severe side effects and even death.…”

Section: Discussionmentioning

confidence: 99%

Wnt/β‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

Zhuang

et al. 2018

Oncol Rep

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Although ~80% of newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL) become disease-free following appropriate treatment, relapses frequently occur, with dismal prognosis. Therefore, it is urgent to develop novel therapeutic modalities. Resistance to chemotherapy is a major obstacle for the treatment of relapsed ALL. It has been indicated that Wnt pathway is potentially associated with leukemia recurrence. In the current study, a vincristine (VCR)-resistant variant of the human ALL cell line BALL-1 (BALL-1/VCR) that also had relatively specific resistance to both doxorubicin and etoposide was generated. Over-activation of the Wnt/β-catenin signaling pathway was observed in BALL-1/VCR cells, whereas Dickkopf-related protein 1 selectively suppressed the Wnt signaling pathway and sensitized the response of BALL-1/VCR to anticancer agents. In addition, prednisolone exposure in combination with Wnt inhibition restored chemo-sensitivity in relapsed ALL blasts. Since the resistance of BALL-1/VCR cells is potentially attributed to the overexpression of MDR-associated protein 1 (MRP1), the development of drug resistance in relapsed ALL may associated with the overexpression of MRP1 and P-glycoprotein. The results of this study demonstrated that, as a potential candidate to mimic relapsed ALL, BALL-1/VCR could be used in further research, while Wnt-inhibition may become a promising therapeutic approach for treating ALL.

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Section: Discussionmentioning

confidence: 99%

Wnt/β‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

Zhuang

et al. 2018

Oncol Rep

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“…Secondly, the trend observed for more relapses (30%) in patients with deletions in BTG1 (BTG anti‐proliferation factor 1) is worthy of note because BTG1 loss has been associated with both steroid resistance and poorer prognosis in the ALLR3 trial for relapsed paediatric ALL (Irving et al , ). In addition, BTG1 deletions appear to accentuate the poor outcome of newly diagnosed patients with IKZF1 deletions (Scheijen et al , ). Finally, the higher relapse rate (33%) for 40 patients with RB1 deletions is also interesting.…”

Section: Discussionmentioning

confidence: 99%

A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B‐cell acute lymphoblastic leukaemia in children

et al. 2017

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To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 + for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 + groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.

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“…The B‐cell translocation gene 1(BTG1) is located on chromosome 12q21 and negatively regulates cell proliferation. Deletions in this gene are found in 10%‐20% of Ph+ ALL cases and are associated with lower rates of DFS and shorter remissions …”

Section: Other Genomic Alterationsmentioning

confidence: 97%

Advances in BCR/ABL positive ALL

Horowitz

Rowe

2019

Adv Cell Gene Ther

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The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Although, as a group, these inhibitors have led to one of the most successful targeted therapies in leukemia, Ph+ ALL still remains a formidable disease. Unlike chronic myeloid leukemia (CML) where TKIs lead to dramatic long‐lasting responses as single agents, the biology of Ph+ ALL is far more complex and adjunctive therapies are mandatory. These may include corticosteroids, chemotherapy, antibody‐based therapies or, even, allogeneic hematopoietic cell transplantation. Clearly, other genes or mutations are in place that affect the outcome of Ph+ ALL. Additional chromosomal abnormalities are common in Ph+ ALL and have a varying impact on prognosis; some adverse, others less so. Genomic alterations have come into their own in the last decade and have increased our understanding of the mechanisms of resistance and differing responses to therapy. In this review, these genetic aberrations will be considered in some detail. In addition, innovations in current practice – including the use of immunological therapies – will be carefully reviewed. For the first time in decades, the long‐held imperative requiring an allogeneic transplant for a curative approach in adult Ph+ ALL is now being questioned and clinical trials are underway to resolve this issue. However, despite much progress in the past two decades, both in the biology and therapy of Ph+ ALL, this disease still presents a compelling challenge and much remains to be overcome.

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Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

Cited by 50 publications

References 46 publications

Wnt/β‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

Wnt/β‑catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B‐cell acute lymphoblastic leukaemia in children

Advances in BCR/ABL positive ALL

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