Rearrangement of CRLF2 in B-progenitor-and Down syndrome-associated acute lymphoblastic leukemia

Charles G. Mullighan, J. Racquel Collins-Underwood, Letha A.A. Phillips, Michael G. Loudin, Wei Liu, Jinghui Zhang, Jing Ma, Elaine Coustan-Smith, Richard C. Harvey, Cheryl L. Willman, Fady M. Mikhail, Julia Meyer, Andrew J. Carroll, Richard T. Williams, Jinjun Cheng, Nyla A. Heerema, Giuseppe Basso, Andrea Pession, Ching Hon Pui, Susana C. RaimondiStephen P. Hunger, James R. Downing, William L. Carroll, Karen R. Rabin

Research output: Contribution to journalArticlepeer-review

519 Scopus citations


Aneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many individuals with this cancer lack recurring chromosomal alterations. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. We identified the P2RY8-CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8-CRLF2 together with mutated mouse Jak2 resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3 cells overexpressing interleukin-7 receptor alpha. Our findings indicate that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.

Original languageEnglish
Pages (from-to)1243-1246
Number of pages4
JournalNature Genetics
Issue number11
StatePublished - Nov 2009
Externally publishedYes


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