Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol.
In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL.
We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions.
In mice xenografted with primary human CRLF2-rearranged B-ALL, JQ1 suppressed c-Myc expression and STAT5 phosphorylation and significantly prolonged survival.
In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor.
We illustrate how PDX models can be optimized to overcome a lack of cross-species cytokine activity by reviewing a recent strategy developed for use with a high-risk form of B-cell acute lymphoblastic leukemia (B-ALL) that is characterized by overexpression of CRLF2, a receptor component for the cytokine, TSLP.
Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B-cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis.
Gene expression profiles of <i>NP23</i> pro-B-1 ALL were more similar to that of <i>CRLF2</i>r ALL than non-<i>CRLF2</i>r ALL, and analysis of V<sub>H</sub> gene usage from patients with <i>CRLF2r</i> ALL demonstrated preferential usage of V<sub>H</sub> regions used by human B-1 B cells, leading to the suggestion that this subset of patients with BCP-ALL has a malignancy of B-1, rather than B-2, B-cell origin.
Detection of genetic alterations in B-ALL, such as CRLF2 rearrangements, may enhance patient risk stratification and therapy options in pediatric B-ALL.
MFC allows a rapid, inexpensive, and reliable detection of B-ALL with CRLF2 rearrangement that would further facilitate testing for JAK2 mutations for targetable therapy.
To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL.
In addition, we use Clinker to explore multiple fusion transcripts with novel breakpoints within the P2RY8-CRLF2 fusion gene in B-cell acute lymphoblastic leukemia.
It has been reported that overexpression of the CRLF2 gene is associated with poor outcomes in pediatric B cell acute lymphoblastic leukemia (B-ALL), but the incidence rates, clinical characteristics and outcomes of CRLF2 gene overexpression in pediatric T cell ALL (T-ALL) have not been systematically analyzed.