Abstract 5026: Protein tyrosine phosphatase Ptpn1 knockout in mouse models drives B-cell hematological malignancies
Bibliographic record
Abstract
Abstract Background: Ptpn1 is a member of Protein Tyrosine Phosphatase family that dephosphorylates tyrosine residues. We previously reported that an Mcm2 hypomorphic mouse (designated Mcm Cre/Cre) develops T cell acute lymphoblastic leukemia (T-ALL), due to acquisition of 100-1000 kb interstitial deletions involving tumor suppressor genes. When crossed to mice that express a NUP98-HOXD13 (NHD13) fusion gene, NHD13+;Mcm2Cre/Cre mice develop B-cell precursor ALL (BCP-ALL). Sparse whole genome sequencing revealed somatic copy number variants (CNV) involving Pax5 and Ptpn1. The role of Pax5 in B-cell development, differentiation, and leukemia has been widely studied. However, little is known about deletions of Ptpn1 and its role in BCP-ALL. Objective: The principal objective is to investigate how deletion of Ptpn1 impacts BCP-ALL development in mouse models. Methods: Mice expressing NHD13 fusion (NHD13+) were crossed with Ptpn1 knockout mice. The F2 cross generated 6 genotypes that were positive or negative for NHD13 and wild type/heterozygous/homozygous for Ptpn1. Mice were studied for incidence of BCP-ALL, which was characterized by whole-exome sequencing, molecular pathway analysis and transcriptome-sequencing. Results: NHD13+;Ptpn1-/- mice developed BCP-ALL, characterized by hyperleukocytosis, variable anemia and thrombocytopenia, expression of B220 and/or CD19, and invasion of non-hematopoietic tissues (liver, kidney, lung). In addition, NHD13+;Ptpn1+/- mice that developed BCP-ALL lost the wild-type (WT) Ptpn1 allele in the leukemic cells. Similar to human BCP-ALL, NHD13+;Ptpn1-/- mice that developed BCP-ALL showed presence of clonal TCR-delta rearrangements as well as IGH rearrangements in the leukemic cells. Whole exome sequencing showed presence of acquired mutations in genes known to be involved in B-cell differentiation, such as Pax5 or Bcor, as well as genes involved in B cell signaling pathways, such as Jak3, Jak1 and Flt3 and Western blots demonstrated accumulation of phosphorylated STAT3 protein. Conclusion: This study demonstrates that Ptpn1 loss along with expression of an NHD13 fusion gene leads to a highly penetrant BCP ALL in mice, suggesting a role for Ptpn1 in preventing malignant transformation. Taken together, these findings are consistent with a collaborative model for BCP ALL in which the NHD13 transgene leads to increased stem cell self-renewal, somatic Bcor or Pax5 mutations block normal B cell differentiation, and somatic signaling mutations (Jak1/3, Flt3) lead to hyperproliferation, which is potentiated by Ptpn1 deficiency. Citation Format: Toshihiro Matsukawa, Nupur Nigam, Ryan Bertoli, Michel L. Tremblay, Mianmian Yin, Peter D. Aplan. Protein tyrosine phosphatase Ptpn1 knockout in mouse models drives B-cell hematological malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5026.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.015 | 0.005 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".