Immunosurveillance of childhood ALL: polymorphic interferon-γ alleles are associated with age at diagnosis and clinical risk groups

Cloppenborg, Thomas; Stanulla, Martin; Zimmermann, Martin; Schrappe, Martin; Welte, Karl; Klein, C

doi:10.1038/sj.leu.2403553

Cited by 21 publications

(14 citation statements)

References 24 publications

(33 reference statements)

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“…The association of gene polymorphisms with ALL risk and the presence of an IFN‐γ response signature in pediatric ALL blasts suggest an influence of the cytokine milieu on leukemia progression. However, the timing of this influence is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…An influence of the resting immune environment, in the absence of infection, on ALL progression has also been suggested, but as yet no mechanisms have been identified. Polymorphisms in cytokine genes can affect basal expression levels and several have been correlated with ALL development . Furthermore, pediatric ALL blasts display an IFN‐γ response signature , and IL‐10 protein levels in neonatal blood spots are independently associated with the risk of developing ALL .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

Fidanza

Seif

et al. 2017

Eur J Immunol

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The early-life immune environment has been implicated as a modulator of acute lymphoblastic leukemia (ALL) development in children, with infection being associated with significant changes in ALL risk. Furthermore, polymorphisms in several cytokine genes, including IL-10 and IFN-γ, are associated with leukemia development. However, the mechanisms and timing of these influences remain unknown. Here, we use the Eμ-ret transgenic mouse model of B-cell precursor ALL to assess the influence of IFN-γ on the early-life burden of leukemia-initiating cells. The absence of IFN-γ activity resulted in greater numbers of leukemia-initiating cells early in life and was associated with accelerated leukemia onset. The leukemia-initiating cells from IFN-γ-knockout mice had reduced suppressor of cytokine signaling (SOCS-1) expression, were significantly more sensitive to IFN-γ, and exhibited more rapid expansion in vivo than their wild-type counterparts. However, sensitivity to this inhibitory pathway was lost in fully transformed IFN-γ-knockout leukemia cells. These results demonstrate that the influence of IFN-γ on ALL progression may not be mediated by selection of nascent transformed cells but rather through a general SOCS-mediated reduction in B-cell precursor proliferation. Thus, while cytokine levels may influence leukemia at multiple points during disease progression, our study indicates a significant early influence of basal, infection-independent cytokine production on leukemogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

Fidanza

Seif

et al. 2017

Eur J Immunol

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“…For instance, it has been shown that during transformation, myeloid cells can reduce their production of granulocyte colony-stimulating factor (G-CSF), IL-15, and IFN-γ. Defects in IFN-γ production have been correlated to a specific polymorphism, which has been also linked to clinical risk parameters (e.g., prednisone response) in patients affected by B-lineage acute lymphocytic leukemia (ALL) (70). Strongly produced by normal myeloid progenitors, the physiological function of IL-15 is to expand and activate effector T and NK cells (71) and to promote the generation of memory stem T cell subset (72).…”

Section: Tumor-extrinsic Mechanisms Of Relapsementioning

confidence: 99%

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

et al. 2020

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Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the "graft-vs.-leukemia" effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.

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“…Cloppenborg et al () performed PCR‐based genotyping on B‐ALL patients and healthy controls to determine if host interferon‐gamma ( IFNG ) expression levels were prognostic. They found that different IFNG alleles correlated with risk group, age at presentation, and response to corticosteroids, suggesting differential effects of IFNG on early response to treatment and immunosurveillance.…”

Section: Mll Translocations and Fusion Proteinsmentioning

confidence: 99%

Predicting relapse risk in childhood acute lymphoblastic leukaemia

Teachey

Hunger

2013

Br J Haematol

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SummaryIntensive multi-agent chemotherapy regimens and the introduction of risk-stratified therapy have substantially improved cure rates for children with acute lymphoblastic leukaemia (ALL). Current risk allocation schemas are imperfect, as some children are classified as lower-risk and treated with less intensive therapy relapse, while others deemed higherrisk are probably over-treated. Most cooperative groups previously used morphological clearance of blasts in blood and marrow during the initial phases of chemotherapy as a primary factor for risk group allocation; however, this has largely been replaced by the detection of minimal residual disease (MRD). Other than age and white blood cell count (WBC) at presentation, many clinical variables previously used for risk group allocation are no longer prognostic, as MRD and the presence of sentinel genetic lesions are more reliable at predicting outcome. Currently, a number of sentinel genetic lesions are used by most cooperative groups for risk stratification; however, in the near future patients will probably be risk-stratified using genomic signatures and clustering algorithms, rather than individual genetic alterations. This review will describe the clinical, biological, and response-based features known to predict relapse risk in childhood ALL, including those currently used and those likely to be used in the near future to risk-stratify therapy.

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Immunosurveillance of childhood ALL: polymorphic interferon-γ alleles are associated with age at diagnosis and clinical risk groups

Cited by 21 publications

References 24 publications

IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

Predicting relapse risk in childhood acute lymphoblastic leukaemia

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