title: Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts.
abstract: The control of mRNA stability plays a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation and tumorigenesis. HNRNPA0, which encodes an RNA-binding protein shown to regulate transcript stability via binding to the AU-rich elements of mRNAs, is located within the commonly deleted segment of 5q31.2 in myeloid neoplasms with a del(5q), and is expressed at haploinsufficient levels in these patients. We show that HNRNPA0 is normally highly expressed in hematopoietic stem cells and exhibits dynamic changes in expression during the course of differentiation. To model HNRNPA0 haploinsufficiency, we used RNAi interference in primary murine cells and an experimental cell system, and found that reduced Hnrnpa0 expression leads to a shift from monocytic towards granulocytic differentiation. Microarray-based global expression profiling revealed that Hnrnpa0 knockdown disproportionally impacts AU-rich containing transcripts and alters expression of myeloid specification genes. In therapy-related myeloid neoplasms with a del(5q), AU-rich containing mRNAs are enriched in transcripts that encode proteins associated with increased growth and proliferation. Our findings implicate haploinsufficiency of HNRNPA0 as one of the key initiating mutations in the pathogenesis of myeloid neoplasms with a del(5q), and suggest that therapies that target AU-rich elements warrant consideration in efforts to develop new mechanism-based treatment strategies.
authors: Department of Pediatrics, Division of Oncology, Johns Hopkins University, Baltimora, MD.
authors: David J
authors: DJ
authors: Young
authors: Department of Medicine and the Comprehensive Cancer Center, University of Chicago, IL astoddar@bsd.uchicago.edu.
authors: Angela
authors: A
authors: Stoddart
authors: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Joy
authors: J
authors: Nakitandwe
authors: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: Shann-Ching
authors: SC
authors: Chen
authors: University of Illinois Cancer Center, Chicago, IL, USA.
authors: Zhijian
authors: Z
authors: Qian
authors: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors: James R
authors: JR
authors: Downing
authors: Department of Medicine and the Comprehensive Cancer Center, University of Chicago, IL.
authors: Michelle M
authors: MM
authors: Le Beau
mesh_terms: D020856:AT Rich Sequence; D000818:Animals; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D016609:Neoplasms, Second Primary / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: C000596429:HNRNPA0 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins