Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background.

Abstract

Approximately 10% of NUP98-PHF23 (NP23) mice develop an aggressive acute lymphoblastic leukemia of B-1 lymphocyte progenitor origin (pro-B1 ALL), accompanied by somatic frameshift mutations of the BCL6 interacting corepressor (Bcor) gene, most commonly within a 9-bp "hotspot" in Bcor exon 8. To determine whether experimentally engineered Bcor mutations would lead to pro-B1 ALL, we used clustered, regularly interspaced, short palindromic repeats-associated protein 9 to introduce a Bcor frameshift mutation into NP23 hematopoietic stem and progenitor cells through the use of Bcor small guide RNAs (Bcor sgRNAs). Recipient mice transplanted with NP23 bone marrow or fetal liver cells that had been transduced with a Bcor sgRNA developed pro-B1 ALL, characterized by a B-1 progenitor immunophenotype, clonal Igh gene rearrangement, and Bcor indel mutation, whereas control recipients did not. Similar to a subset of human B-cell precursor ALL, the murine pro-B1 ALL had acquired somatic mutations in Jak kinase genes. JAK inhibitors (ruxolitinib and tofacitinib) inhibited the growth of pro-B1 ALL cell lines established from Bcor sgRNA/NP23 recipients at clinically achievable concentrations (100 nM). Our results demonstrate that Bcor mutations collaborate with NP23 to induce pro-B1 ALL, and that JAK inhibitors are potential therapies for pro-B1 ALL.

• Authors: Mianmian Yin, Yang Jo Chung, R Coleman Lindsley, Robert L Walker, Yuelin J Zhu, Benjamin L Ebert, Paul S Meltzer, Peter D Aplan
• Journal: Blood (Blood) Vol. 133 Issue 24 Pg. 2610-2614 (06 13 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30992267 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Bcor protein, mouse
• Janus Kinase Inhibitors
• Nuclear Pore Complex Proteins
• Oncogene Proteins, Fusion
• Repressor Proteins
• nuclear pore complex protein 98
• Janus Kinases

Topics

• Animals
• B-Lymphocyte Subsets (metabolism, pathology)
• Frameshift Mutation
• Janus Kinase Inhibitors (pharmacology)
• Janus Kinases (antagonists & inhibitors, genetics)
• Mice
• Mice, Transgenic
• Nuclear Pore Complex Proteins (genetics)
• Oncogene Proteins, Fusion (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics)
• Precursor Cells, B-Lymphoid (metabolism, pathology)
• Repressor Proteins (genetics)