Single-cell analysis identifies CRLF2 rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia.
Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown.
These findings demonstrate that surface CRLF2 expression is associated with increased risk of relapse in pediatric BCP-ALL patients harboring <i>IKZF1</i> deletions.
The multiplex ligation-dependent probe amplification (MLPA) method was used to detect the copy number alterations (CNAs) of IKAROS family zinc finger 1 (<i>IKZF1</i>), paired box 5 (<i>PAX5</i>), ETS variant 6 (<i>ETV6</i>), RB transcriptional corepressor 1 (<i>RB1</i>), BTG anti-proliferation factor 1 (<i>BTG1</i>), early B-cell factor 1 (<i>EBF1</i>), cyclin dependent kinase inhibitor 2A/2B (<i>CDKN2A/2B</i>) and cytokine receptor like factor 2 (<i>CRLF2</i>) genes in 87 adults with acute lymphoblastic leukemia (ALL) in China.
Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions.
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.
Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement.
For an overall characterization of pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis of CRLF2 in 167 pediatric BCPALL patients.
We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2-JAK pathway genetic alterations and recurrent gene deletions in Japanese DS-ALL patients.
Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor α (IL7R) or cytokine receptor-like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias.
Activating mutations that target JAK2, as well as JAK1, or CRLF2 and IL7RA, two cytokine receptors with which the JAKs associate in lymphoid cells, have now been identified in a subset of pediatric patients diagnosed with acute lymphoblastic leukemia (ALL), many of whom have a poor prognosis.
The PI3K/mTOR pathway inhibitors rapamycin, PI103, and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway, suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing.