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RINF maintenance of SMAD7 sustains human erythropoiesis
Table 1. List of genes located at 5q and their correlation with SMAD7 expression in primary human CD34+ cells isolated from bone marrow of healthy donors (n=17).
continued from the previous column
242303_at 229936_at 242265_at 216914_at 240966_at
0.122 High-Risk CDR 0.114 High-Risk CDR 0.096 High-Risk CDR 0.083 High-Risk CDR 0.052 Low-Risk CDR 0.041 High-Risk CDR 0.041 High-Risk CDR 0.040 Low-Risk CDR 0.028 High-Risk CDR 0.013 High-Risk CDR -0.018 High-Risk CDR -0.025 High-Risk CDR -0.035 High-Risk CDR -0.068 Low-Risk CDR -0.081 High-Risk CDR -0.094 High-Risk CDR -0.116 High-Risk CDR -0.137 High-Risk CDR -0.143 High-Risk CDR -0.157 High-Risk CDR -0.169 High-Risk CDR -0.179 High-Risk CDR -0.187 High-Risk CDR -0.191 Low-Risk CDR -0.221 High-Risk CDR -0.241 High-Risk CDR -0.315 Low-Risk CDR -0.319 High-Risk CDR -0.351 High-Risk CDR -0.386 High-Risk CDR -0.538 High-Risk CDR -0.559 Low-Risk CDR -0.614 Low-Risk CDR -0.786 High-Risk CDR
Gene name
CXXC5 CXXC5 HSPA9 CXXC5 ETF1 IL17B SPARC ETF1 MATR3 CD74 TGFBI PDGFRB EGR1 SIL1 PSD2 UBE2D2 AFAP1L1 SH3TC2 CSF1R TMEM173 PAIP2 HNRNPA0 CDX1 EGR1 FAM53C AFAP1L1 MZB1 CARMN CDC23 CTNNA1 REEP2 SPATA24 RPS14 LRRTM2
Probeset
222996_s_at 233955_x_at 200690_at 224516_s_at 201574_at 220273_at 212667_at 201573_s_at 238993_at 1567627_at 201506_at 202273_at 201694_s_at 218436_at 223536_at 201345_s_at 1555542_at 233561_at 203104_at 224916_at 222983_s_at 229083_at 206430_at 201693_s_at 218023_s_at 226955_at 223565_at 231987_at 223651_x_at 200764_s_at 205331_s_at 238027_at 208645_s_at 206408_at
Pearson's (correl coeff.)
NRG2
GFRA3
BRD8
CDC25C
SH3TC2
HNRNPA0 201055_s_at KDM3B 210878_s_at GRPEL2 238427_at TMEM173 224929_at EGR1 227404_s_at
0.819 0.784 0.729 0.705 0.640 0.554 0.532 0.508 0.452 0.424 0.422 0.391 0.373 0.355 0.352 0.350 0.343 0.337 0.335 0.312 0.289 0.271 0.259 0.214 0.193 0.184 0.180 0.180 0.178 0.176 0.167 0.137 0.134 0.128
Gene location at 5q
High-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
Low-Risk CDR
Low-Risk CDR
High-Risk CDR
High-Risk CDR
Low-Risk CDR
High-Risk CDR
Low-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
Low-Risk CDR
Low-Risk CDR
Low-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
Low-Risk CDR
High-Risk CDR
High-Risk CDR
Low-Risk CDR
High-Risk CDR
Low-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
High-Risk CDR
Low-Risk CDR
High-Risk CDR
continued in the next column
227166_at 218518_at 208589_at 205730_s_at 206197_at 1555110_a_at 224259_at 1558641_at 207409_at 208193_at 227780_s_at 221221_s_at 221118_at 228144_at 225223_at 202363_at 219710_at 223732_at 205167_s_at 219728_at 201344_at
DNAJC18
FAM13B
TRPC7
ABLIM3
NME5
KLHL3
WNT8A
SPATA24
LECT2
IL9
ECSCR
KLHL3
PKD2L2
ZNF300
SMAD5
TRPC7
SH3TC2
SLC23A1
CDC25C
MYOT
UBE2D2
PCYOX1L 218953_s_at GRPEL2 226881_at KIF20A 218755_at
cells. The role of RINF that we describe here could pave the way to future studies that will be necessary to better understand the complex molecular epigenetic events that occur during normal and ineffective erythropoiesis12,15,48,58 and that may involve TET enzymes.59
Several correlative studies have implicated RINF as a candidate in the pathogenesis of MDS/AML.1,3,5,60 MDS is a complex and heterogeneous malignant hematologic dis- order in which the loss of several genes is suspected to lead to the pathophysiology.4 CXXC5 is located at chro- mosome 5q31.2, in a commonly deleted region associated with high risk in MDS and AML (Online Supplementary Figure S1).1,4 Even though it is uncertain that RINF loss of expression in itself can cause the development of preleukemia, our functional data in human CD34+ cells indicate that loss of RINF may exacerbate cytopenia of
All the genes were selected because they are located within one of the two common- ly deleted regions (CDR) at chromosome 5q. Their mRNA expression level was extracted from a GDS3795 microarray study performed by Pellagatti et al.46 For each gene,a Pearson correlation coefficient was calculated by comparing its expression to the one of SMAD7, and the list is ranked by descending order.
the erythroid lineage. Of importance, the functional con- tribution of Cxxc5/Rinf loss of function to MDS develop- ment was recently described in a mouse model, in which its invalidation (by random insertional mutation) was demonstrated to cooperate with Egr1 haploinsufficiency to promote MDS.4 This study indicated that the Cxxc5 gene could act as a tumor suppressor gene contributing to del(5q) myeloid neoplasms. Although RINF/CXXC5 is not frequently mutated in patients with MDS/AML,60 several recurrent chromosomal anomalies or gene muta- tions could lead to RINF loss of expression and contribute in the long-term to ineffective erythropoiesis and/or myeloid transformation (legend of Online Supplementary Figure S7).
Our findings point to a molecular mechanism in which RINF functions as a negative modulator of TGFb signaling
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