Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice

Thomas, Kerri R.; Allenspach, Eric J.; Camp, Nathan D.; Wray-Dutra, Michelle N.; Khim, Socheath; Zielinska-Kwiatkowska, Anna; Timms, Andrew E.; Loftus, Joseph P.; Liggitt, H. Denny; Georgopoulos, Katia; Tasian, Sarah K.; James, Richard G.; Rawlings, David J.

doi:10.1038/s41375-021-01326-x

Cited by 26 publications

(23 citation statements)

References 127 publications

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“…1 ( 31 ), and Hep3 expressing msmo1 ( 23 ) and hmgcs1 ( 23 ). The immune cell types identified included lymphocytes (expressing zap70 ( 32 ), il7r ( 33 ) and ifng1 ( 34 )), neutrophils/monocytes (expressing mmp13a ( 35 ), mmp9 ( 36 ), lyz ( 37 ) and lect2l ( 38 )), and eosinosphils (expressing viml ( 39 ), hp ( 39 ), cd81a ( 39 ) and gata2a ( 39 )). Marco ( 40 ), cxcl8a ( 41 ) and csf1ra ( 42 ) were highly expressed in noninflammatory macrophages, while grn1 ( 43 ), mpeg1 .…”

Section: Resultsmentioning

confidence: 99%

“…Nonimmune cell types primarily consisted of three hepatocyte subclusters: Hepatocyte (Hep) 1 expressing aqp12 (27) and itih2 (28), Hep 2 expressing ahsg1 (29), apoa1a (30) and apoa4b.1 (31), and Hep3 expressing msmo1 (23) and hmgcs1 (23). The immune cell types identified included lymphocytes (expressing zap70 (32), il7r (33) and ifng1 (34)), neutrophils/monocytes (expressing mmp13a (35), mmp9 (36), lyz (37) and lect2l (38)), and eosinosphils (expressing viml (39), hp (39), cd81a (39) and gata2a (39)). Marco (40), cxcl8a (41) and csf1ra (42) were highly expressed in noninflammatory macrophages, while grn1 (43), mpeg1.1 (44) and cxcr4b (45) were predominantly expressed in inflammatory macrophages.…”

Section: Single-cell Atlas Of Zebrafish Liversmentioning

confidence: 99%

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Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

Huang

Liu

Wang

et al. 2022

Preprint

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Zebrafish have emerged as an attractive animal model for studying nonalcoholic fatty liver disease (NAFLD). However, little is known about the cell types and intercellular interactions in zebrafish liver. Here, we established a liver atlas that consists of 10 cell types using single-cell RNA sequencing. By examining the heterogeneity of hepatocytes and analyzing the expression of NAFLD-associated genes in the specific cluster, we provide a potential target cell model to study NAFLD. Additionally, our analysis identified two distinct resident macrophages with inflammatory and noninflammatory functions and characterized the successive stepwise development of T cell subtypes in the liver. Importantly, we uncovered possible molecular mechanisms and revealed the central regulation of macrophages on target cells of fatty liver by analyzing the cellular interaction between hepatocytes and immune cells. Our data provide valuable information for future research on NAFLD in zebrafish.

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Section: Resultsmentioning

confidence: 99%

Section: Single-cell Atlas Of Zebrafish Liversmentioning

confidence: 99%

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

Huang

Liu

Wang

et al. 2022

Preprint

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“…Here, we wished to determine whether IL7RA signaling has any role in the initiation of human BCP-ALL and, if so, how the receptor activation-driven B-cell precursors are predisposed to transformation. Recent research described the ability of IL7RA activation to initiate B-cell precursor ALL 40 , 41 in mouse hematopoietic cells. However, due to the potential different functions of IL7 signaling in B-cell development in mice and humans and given the heterogeneous phenotypes of IL7RA perturbations in mice 8 – 11 , 42 – 44 , we chose to establish an experimental model that authentically re-capitulate disease initiation and progression in relevant human cells.…”

Section: Discussionmentioning

confidence: 99%

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

et al. 2022

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Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

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“…Using a conditional knock-in mouse model, Almeida et al showed that physiological levels of mutant IL-7Rα were sufficient to generate preleukemic B cell precursors and to initiate leukemia resembling the human Ph-like and PAX5 P80R ALL subtypes [ 87 ]. Thomas et al generated a genetically engineered mouse model with B cell-intrinsic expression of mutant IL7R that presented with development of BCP-ALL [ 88 ]. In an elegant study, Geron et al transduced human CD34 + hematopoietic cells with mutant IL-7Rα.…”

Section: Interleukin-7 Receptor α (Il-7rα) Mutations In Bcp-all Devel...mentioning

confidence: 99%

“…These led to upregulation of IL-7R signaling (via the JAK/STAT5 or the PI3K/mTOR pathway), upregulation of oncogenes (e.g., MYC, BCL2 ), and downregulation of tumor suppressors (including IKZF1 ) [ 87 – 89 ]. Additionally, CDKN2A was silenced [ 89 ••], and recurrent somatic KRAS mutations which cooperate with mutant IL7R were observed [ 87 , 88 ].…”

Section: Interleukin-7 Receptor α (Il-7rα) Mutations In Bcp-all Devel...mentioning

confidence: 99%

In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia

Rüchel

Jepsen

Hein

et al. 2022

Curr. Treat. Options in Oncol.

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Opinion statementAcute lymphoblastic leukemia (ALL) is the most frequent type of pediatric cancer with a peak incidence at 2–5 years of age. ALL frequently begins in utero with the emergence of clinically silent, preleukemic cells. Underlying leukemia-predisposing germline and acquired somatic mutations define distinct ALL subtypes that vary dramatically in treatment outcomes. In addition to genetic predisposition, a second hit, which usually occurs postnatally, is required for development of overt leukemia in most ALL subtypes. An untrained, dysregulated immune response, possibly due to an abnormal response to infection, may be an important co-factor triggering the onset of leukemia. Furthermore, the involvement of natural killer (NK) cells and T helper (Th) cells in controlling the preleukemic cells has been discussed. Identifying the cell of origin of the preleukemia-initiating event might give additional insights into potential options for prevention. Modulation of the immune system to achieve prolonged immunosurveillance of the preleukemic clone that eventually dies out in later years might present a future directive. Herein, we review the concepts of prenatal origin as well as potential preventive approaches to pediatric B cell precursor (BCP) ALL.

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Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice

Abstract: Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice.

Cited by 26 publications

References 127 publications

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

In Utero Development and Immunosurveillance of B Cell Acute Lymphoblastic Leukemia

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