Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways

Area of Science:

• Immunology
• Hematology
• Oncology

Background:

• B-1 and B-2 lymphocytes originate from distinct developmental pathways.
• Most murine B-cell malignancies are B220-positive, unlike the novel leukemia discovered.

Purpose of the Study:

• To characterize a novel B-cell leukemia in NUP98-PHF23 (NP23) transgenic mice.
• To investigate the developmental origin and genetic underpinnings of this leukemia.
• To explore the relationship between this murine model and human B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Main Methods:

• Immunophenotyping (Lin-, B220-, CD19+, AA4.1+).
• V H gene usage analysis.
• Gene expression profiling.
• Analysis of spontaneous mutations in Bcor and Janus kinase (Jak) pathway genes.

Main Results:

• The leukemia exhibited an immunophenotype identical to progenitor (pro) B-1 cells.
• V H gene usage and gene expression profiles were similar to fetal liver B-1 cells.
• Leukemias acquired mutations in Bcor and Jak pathway genes, suggesting collaborative roles in oncogenesis.
• NP23 pro-B-1 ALL gene expression profiles closely resembled human CRLF2-rearranged (CRLF2r) ALL.
• CRLF2r ALL patients showed preferential usage of V H regions characteristic of human B-1 cells.

Conclusions:

• The novel murine leukemia originates from pro-B-1 cells.
• Mutations in stem-cell self-renewal, B-cell differentiation, and cytokine signaling pathways collaborate to induce BCP-ALL.
• A subset of human BCP-ALL, specifically CRLF2r ALL, may represent a malignancy of B-1 cell origin, distinct from the more common B-2 cell origin.