Investigating the role of CRLF2/JAK2 Signalling in high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL)

Chromosomal translocations leading to overexpression of the cytokine receptor CRLF2 frequently occur in B-cell ALL (B-ALL), and this is closely linked with activating mutations of JAK2 kinase and adverse prognosis. Overexpressed CRLF2 and mutant JAK2 physically associate resulting in activation of important oncogenic pathways.

To investigate the functional role of CRLF2 and JAK2 mutations during leukemia initiation, the laboratory generated transgenic mice expressing murine CRLF2 under the control of the immunoglobulin heavy chain enhancer (Eµ) to enforce lymphoid-specific expression of our transgene. We retrovirally transduced fetal liver stem cells from day E13.5 embryos of Eµ-mCRLF2 transgenic mice with GFP-tagged constructs expressing JAK2WT, JAK2R683G, JAK2P933R or an empty vector, followed by transplantation into irradiated recipient mice. Cohorts transplanted with Eµ-CRLF2 fetal liver cells expressing mutant JAK2 exclusively developed leukemia characterized by hepatosplenomegaly, expansion of c-kit+ GFP+ blasts, and exhibited constitutive JAK-STAT signaling. Hence, our results demonstrate that CRLF2 overexpression and mutant JAK2 cooperate during leukemia initiation.

This project aims to investigate how CRLF2 and JAK2 cooperate in the initiation and progression of B-ALL, and to develop novel therapeutic strategies to treat tumors with aberrant CRLF2/JAK2 signaling.


The Johnstone laboratory fully integrates fundamental cancer and immunological research and pre-clinical development and testing of novel therapeutic regimes to drive new clinical trials using agents under investigation in our lab.

Major themes include: defining the molecular events underpinning anti-cancer drug action and resistance; dissecting the role of altered epigenetics in tumor onset and progression and targeting epigenetic enzymes to treat cancer; and integrating epigenetic- and immune-based therapeutics to provide more potent and durable therapeutic outcomes.