Gain of chromosome 21 increases the propensity for acute lymphoblastic leukemia increased expression.

Acute lymphoblastic leukemia (ALL) patients with a gain of chromosome 21, intrachromosomal amplification of chromosome 21 (iAMP21), or Down syndrome (DS), have increased expression of genes in the DS critical region (DSCR) of chromosome 21, including the high-mobility group nucleosome-binding protein 1, . Children with DS are predisposed to develop hematologic malignancies, providing insight into the role of chromosome 21 in the development of leukemias. A 320-kb deletion in the pseudoautosomal region of the X/Y chromosome in leukemic cells, resulting in a gene fusion between the purinergic receptor and cytokine receptor-like factor-2 (), is a common feature in ~60% of DS-ALL and ~40% of iAMP21 patients, suggesting a link between chromosome 21 and . In an Australian cohort of pediatric B-ALL patients with ( = 38), eight patients harbored gain of chromosome 21 (+21), and two patients had iAMP21, resulting in a significantly increased expression. An inducible CRISPR/Cas9 system was used to model and investigate its cooperation with . This model was then used to validate as an influencing factor for development. Using Cas9 to cleave the DNA at the pseudoautosomal region without directed repair, cells expressing favored repair, resulting in generation, compared with cells without . CRISPR/Cas9 cells expressing exhibit increased proliferation, thymic stromal lymphopoietin receptor (TSLPR) expression, and JAK/STAT signaling, consistent with cells from patients with . Our patient expression data and unique CRISPR/Cas9 modeling, when taken together, suggest that increases the propensity for development. This has important implications for patients with DS, +21, or iAMP21.