Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia.
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.
Mullighan
Charles G
CG
Collins-Underwood
J Racquel
JR
Phillips
Letha A A
LA
Loudin
Michael G
MG
Liu
Wei
W
Zhang
Jinghui
J
Ma
Jing
J
Coustan-Smith
Elaine
E
Harvey
Richard C
RC
Willman
Cheryl L
CL
Mikhail
Fady M
FM
Meyer
Julia
J
Carroll
Andrew J
AJ
Williams
Richard T
RT
Cheng
Jinjun
J
Heerema
Nyla A
NA
Basso
Giuseppe
G
Pession
Andrea
A
Pui
Ching-Hon
CH
Raimondi
Susana C
SC
Hunger
Stephen P
SP
Downing
James R
JR
Carroll
William L
WL
Rabin
Karen R
KR
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002872:Chromosome Deletion; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D015321:Gene Rearrangement; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000235:genetics*; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
C498762:CRLF2 protein, human; D018121:Receptors, Cytokine; D018048:Receptors, Purinergic P2; D011993:Recombinant Fusion Proteins; D053614:Janus Kinase 2