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Acute lymphoblastic leukemia

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

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite the absence of surface pre-BCR. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this mouse model of IL7R-driven B-ALL.

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Fig. 1: B-intrinsic aIL7R and heterozygous loss of Sh2b3 or Ikaros rapidly promote B cell precursor leukemias.
Fig. 2: aIL7R leukemias are transplantable into immunocompetent hosts and acquire mutations in clinically relevant genes.
Fig. 3: B-lineage aIL7R cooperates with heterozygous loss of Sh2b3 or Ikzf1 to drive a specific expansion of late pro B cells.
Fig. 4: aIL7R with Sh2b3 loss promotes enhanced survival in normal and leukemic B cell progenitors.
Fig. 5: aIL7R-expressing B cell progenitors are less sensitive to IL-7 depletion in vivo.
Fig. 6: aIL7R leukemias are responsive to rapamycin therapy in vivo.
Fig. 7: IL-7R-mutant leukemias display activation of a “BCR-like” signaling program.

Data availability

The mapped reads for the whole-exome sequencing have been deposited in the Sequence Read Archive database (BioProject ID: PRJNA735253). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [63] partner repository with the dataset identifiers PXD026438 and PXD026322.

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Acknowledgements

The authors would like to thank Karen Sommer and Andrea Repele for laboratory management, Jennifer Haddock for administrative support, Beth Lawlor for helpful comments and critical review of the manuscript, the University of Washington Histology and Imaging Core, and the Northwest Genomics Center at the University of Washington. This work was supported by the National Institutes of Health under award numbers: TL1-TR000422 (to KRT), DP3-DK111802 (to DJR), NCI-R01CA201135-A1 (to RGJ), 1K08CA184418 (to SKT), 1U01CA232486 (to SKT), 1U01CA243072 (SKT), 1K08DK114568-01 (to EJA), Department of Defense Translational Team Science Award CA180683P1 (to SKT), the V Foundation for Cancer Research (to SKT), the Seattle Children’s Research Institute (SCRI) Center for Immunity and Immunotherapies (CIIT) Program for Cell and Gene Therapy (PCGT), the Children’s Guild Association Endowed Chair in Pediatric Immunology (to DJR), and the Hansen Investigator in Pediatric Innovation Endowment (to DJR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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KRT, EJA, and NDC: designed and performed experiments, analyzed data, and wrote and/or edited the manuscript. KRT and EJA designed the aIL7R murine model. MNW, JPL, SK, and AZ: designed, performed, and interpreted the experiments. AET and HDL analyzed data. KG provided the Ikzf1 flox mice and edited the manuscript. SKT provided the PDX models, interpreted data, and edited the manuscript. RGJ and DJR conceived of and supervised the study, interpreted data, and edited the manuscript.

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Correspondence to Richard G. James or David J. Rawlings.

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SKT receives research funding from Incyte Corporation, Gilead Sciences, and MacroGenics, Inc. for unrelated studies and is a member of the scientific advisory board of Aleta Biotherapeutics for unrelated studies.

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Thomas, K.R., Allenspach, E.J., Camp, N.D. et al. Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice. Leukemia (2021). https://doi.org/10.1038/s41375-021-01326-x

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