0	21	1,25-Dihydroxyvitamin	1,25-Dihydroxyvitamin	NNP
22	24	D3	D3	NNP
25	32	induces	induce	VBZ
33	48	differentiation	differentiation	NN
49	51	of	of	IN
52	53	a	a	DT
54	62	retinoic	retinoic	JJ
63	77	acid-resistant	acid-resistant	JJ
78	83	acute	acute	JJ
84	97	promyelocytic	promyelocytic	JJ
98	106	leukemia	leukemia	NN
107	111	cell	cell	NN
112	116	line	line	NN
117	118	(	(	(
118	122	UF-1	uf-1	NN
122	123	)	)	)
124	134	associated	associate	VBN
135	139	with	with	IN
140	150	expression	expression	NN
151	153	of	of	IN
154	168	p21(WAF1/CIP1)	p21(WAF1/CIP1)	NNP
169	172	and	and	CC
173	182	p27(KIP1)	p27(KIP1)	NNP
182	183	.	.	.

185	193	Retinoic	retinoic	JJ
194	198	acid	acid	NN
199	200	(	(	(
200	202	RA	RA	NNP
202	203	)	)	)
204	214	resistance	resistance	NN
215	217	is	be	VBZ
218	219	a	a	DT
220	227	serious	serious	JJ
228	235	problem	problem	NN
236	239	for	for	IN
240	248	patients	patient	NNS
249	253	with	with	IN
254	259	acute	acute	JJ
260	273	promyelocytic	promyelocytic	JJ
274	282	leukemia	leukemia	NN
283	284	(	(	(
284	287	APL	APL	NNP
287	288	)	)	)
289	292	who	who	WP
293	296	are	be	VBP
297	306	receiving	receive	VBG
307	316	all-trans	all-trans	JJ
317	319	RA	RA	NNP
319	320	.	.	.

321	328	However	however	RB
328	329	,	,	,
330	333	the	the	DT
334	344	mechanisms	mechanism	NNS
345	348	and	and	CC
349	359	strategies	strategy	NNS
360	362	to	to	TO
363	371	overcome	overcome	VB
372	374	RA	RA	NNP
375	385	resistance	resistance	NN
386	388	by	by	IN
389	392	APL	APL	NNP
393	398	cells	cell	NNS
399	402	are	be	VBP
403	408	still	still	RB
409	416	unclear	unclear	JJ
416	417	.	.	.

418	421	The	the	DT
422	430	biologic	biologic	JJ
431	438	effects	effect	NNS
439	441	of	of	IN
442	444	RA	RA	NNP
445	448	are	be	VBP
449	457	mediated	mediate	VBN
458	460	by	by	IN
461	464	two	two	CD
465	473	distinct	distinct	JJ
474	482	families	family	NNS
483	485	of	of	IN
486	501	transcriptional	transcriptional	JJ
502	509	factors	factor	NNS
509	510	:	:	:
511	513	RA	RA	NNP
514	523	receptors	receptor	NNS
524	525	(	(	(
525	529	RARs	RAR	NNPS
529	530	)	)	)
531	534	and	and	CC
535	543	retinoid	retinoid	NN
544	545	X	X	NNP
546	555	receptors	receptor	NNS
556	557	(	(	(
557	561	RXRs	RXR	NNP
561	562	)	)	)
562	563	.	.	.

564	568	RXRs	rxr	NNS
569	583	heterodimerize	heterodimerize	VBP
584	588	with	with	IN
589	590	1	1	CD
590	591	,	,	,
592	611	25-dihydroxyvitamin	25-dihydroxyvitamin	NN
612	614	D3	D3	NNP
615	616	[	[	(
616	627	1,25(OH)2D3	1,25(OH)2D3	NNP
627	628	]	]	)
629	637	receptor	receptor	NN
638	639	(	(	(
639	642	VDR	VDR	NNP
642	643	)	)	)
643	644	,	,	,
645	653	enabling	enable	VBG
654	659	their	their	PRP$
660	669	efficient	efficient	JJ
670	685	transcriptional	transcriptional	JJ
686	696	activation	activation	NN
696	697	.	.	.

698	701	The	the	DT
702	718	cyclin-dependent	cyclin-dependent	JJ
719	725	kinase	kinase	NNP
726	727	(	(	(
727	730	cdk	cdk	NN
730	731	)	)	)
732	741	inhibitor	inhibitor	NN
742	756	p21(WAF1/CIP1)	p21(waf1/cip1)	NN
757	760	has	have	VBZ
761	762	a	a	DT
763	770	vitamin	vitamin	NN
771	784	D3-responsive	d3-responsive	JJ
785	792	element	element	NN
793	794	(	(	(
794	798	VDRE	VDRE	NNP
798	799	)	)	)
800	802	in	in	IN
803	806	its	its	PRP$
807	815	promoter	promoter	NN
815	816	,	,	,
817	820	and	and	CC
821	832	1,25(OH)2D3	1,25(OH)2D3	NNP
833	841	enhances	enhance	VBZ
842	845	the	the	DT
846	856	expression	expression	NN
857	859	of	of	IN
860	874	p21(WAF1/CIP1)	p21(WAF1/CIP1)	NNP
875	878	and	and	CC
879	886	induces	induce	VBZ
887	902	differentiation	differentiation	NN
903	905	of	of	IN
906	914	selected	select	VBN
915	922	myeloid	myeloid	JJ
923	931	leukemic	leukemic	JJ
932	936	cell	cell	NN
937	942	lines	line	NNS
942	943	.	.	.

944	946	We	we	PRP
947	951	have	have	VBP
952	960	recently	recently	RB
961	972	established	establish	VBN
973	974	a	a	DT
975	980	novel	novel	JJ
981	984	APL	APL	NNP
985	989	cell	cell	NN
990	994	line	line	NN
995	996	(	(	(
996	1000	UF-1	uf-1	NN
1000	1001	)	)	)
1002	1006	with	with	IN
1007	1015	features	feature	NNS
1016	1018	of	of	IN
1019	1021	RA	RA	NNP
1022	1033	resistance.	resistance.	NN
1034	1045	1,25(OH)2D3	1,25(OH)2D3	NNP
1046	1049	can	can	MD
1050	1056	induce	induce	VB
1057	1063	growth	growth	NN
1064	1074	inhibition	inhibition	NN
1075	1078	and	and	CC
1079	1081	G1	g1	NN
1082	1088	arrest	arrest	NN
1089	1091	of	of	IN
1092	1096	UF-1	uf-1	NN
1097	1102	cells	cell	NNS
1102	1103	,	,	,
1104	1113	resulting	result	VBG
1114	1116	in	in	IN
1117	1132	differentiation	differentiation	NN
1133	1135	of	of	IN
1136	1141	these	these	DT
1142	1147	cells	cell	NNS
1148	1154	toward	toward	IN
1155	1167	granulocytes	granulocyte	NNS
1167	1168	.	.	.

1169	1173	This	this	DT
1174	1175	1	1	CD
1175	1176	,	,	,
1177	1194	25(OH)2D3-induced	25(oh)2d3-induced	JJ
1195	1197	G1	g1	NN
1198	1204	arrest	arrest	NN
1205	1207	is	be	VBZ
1208	1216	enhanced	enhance	VBN
1217	1219	by	by	IN
1220	1229	all-trans	all-trans	JJ
1230	1232	RA	RA	NNP
1232	1233	.	.	.

1234	1238	Also	also	RB
1238	1239	,	,	,
1240	1241	1	1	CD
1241	1242	,	,	,
1243	1252	25(OH)2D3	25(OH)2D3	NNP
1253	1254	(	(	(
1254	1261	10(-10)	10(-10)	CD
1262	1264	to	to	TO
1265	1271	10(-7)	10(-7)	CD
1272	1277	mol/L	mol/l	NN
1277	1278	)	)	)
1279	1281	in	in	IN
1282	1293	combination	combination	NN
1294	1298	with	with	IN
1299	1301	RA	RA	NNP
1302	1310	markedly	markedly	RB
1311	1319	inhibits	inhibit	VBZ
1320	1328	cellular	cellular	JJ
1329	1342	proliferation	proliferation	NN
1343	1345	in	in	IN
1346	1347	a	a	DT
1348	1353	dose-	dose-	NN
1354	1357	and	and	CC
1358	1372	time-dependent	time-dependent	JJ
1373	1379	manner	manner	NN
1379	1380	.	.	.

1381	1391	Associated	associate	VBN
1392	1396	with	with	IN
1397	1402	these	these	DT
1403	1411	findings	finding	NNS
1411	1412	,	,	,
1413	1416	the	the	DT
1417	1423	levels	level	NNS
1424	1426	of	of	IN
1427	1441	p21(WAF1/CIP1)	p21(WAF1/CIP1)	NNP
1442	1445	and	and	CC
1446	1455	p27(KIP1)	p27(KIP1)	NNP
1456	1460	mRNA	mRNA	NNP
1461	1464	and	and	CC
1465	1472	protein	protein	NN
1473	1482	increased	increase	VBD
1483	1485	in	in	IN
1486	1491	these	these	DT
1492	1497	cells	cell	NNS
1497	1498	.	.	.

1499	1507	Northern	Northern	NNP
1508	1512	blot	blot	NN
1513	1521	analysis	analysis	NN
1522	1528	showed	show	VBD
1529	1533	that	that	IN
1534	1548	p21(WAF1/CIP1)	p21(WAF1/CIP1)	NNP
1549	1552	and	and	CC
1553	1562	p27(KIP1)	p27(KIP1)	NNP
1563	1567	mRNA	mRNA	NNP
1568	1571	and	and	CC
1572	1579	protein	protein	NN
1580	1589	increased	increase	VBD
1590	1592	in	in	IN
1593	1598	these	these	DT
1599	1604	cells	cell	NNS
1604	1605	.	.	.

1606	1614	Northern	Northern	NNP
1615	1619	blot	blot	NN
1620	1628	analysis	analysis	NN
1629	1635	showed	show	VBD
1636	1640	that	that	IN
1641	1655	p21(WAF1/CIP1)	p21(WAF1/CIP1)	NNP
1656	1659	and	and	CC
1660	1669	p27(KIP1)	p27(kip1)	NN
1670	1681	transcripts	transcript	NNS
1682	1686	were	be	VBD
1687	1694	induced	induce	VBN
1695	1700	after	after	IN
1701	1702	6	6	CD
1703	1708	hours	hour	NNS
1708	1709	’	'	POS
1710	1718	exposure	exposure	NN
1719	1721	to	to	TO
1722	1733	1,25(OH)2D3	1,25(OH)2D3	NNP
1734	1737	and	and	CC
1738	1742	then	then	RB
1743	1752	decreased	decrease	VBD
1753	1755	to	to	TO
1756	1761	basal	basal	JJ
1762	1768	levels	level	NNS
1769	1773	over	over	IN
1774	1776	48	48	CD
1777	1782	hours	hour	NNS
1782	1783	.	.	.

1784	1791	Western	western	JJ
1792	1796	blot	blot	NN
1797	1808	experiments	experiment	NNS
1809	1815	showed	show	VBD
1816	1820	that	that	IN
1821	1835	p21(WAF1/CIP1)	p21(waf1/cip1)	NN
1836	1843	protein	protein	NN
1844	1850	levels	level	NNS
1851	1860	increased	increase	VBD
1861	1864	and	and	CC
1865	1871	became	become	VBD
1872	1882	detectable	detectable	JJ
1883	1888	after	after	IN
1889	1891	12	12	CD
1892	1897	hours	hour	NNS
1898	1900	of	of	IN
1901	1912	1,25(OH)2D3	1,25(oh)2d3	NN
1913	1922	treatment	treatment	NN
1923	1926	and	and	CC
1927	1936	induction	induction	NN
1937	1939	of	of	IN
1940	1949	p27(KIP1)	p27(kip1)	NN
1950	1957	protein	protein	NN
1958	1961	was	be	VBD
1962	1966	much	much	RB
1967	1971	more	more	RBR
1972	1979	gradual	gradual	JJ
1980	1983	and	and	CC
1984	1993	sustained	sustained	JJ
1994	1996	in	in	IN
1997	2001	UF-1	uf-1	NN
2002	2007	cells	cell	NNS
2007	2008	.	.	.

2009	2022	Interestingly	interestingly	RB
2022	2023	,	,	,
2024	2027	the	the	DT
2028	2039	combination	combination	NN
2040	2042	of	of	IN
2043	2044	1	1	CD
2044	2045	,	,	,
2046	2055	25(OH)2D3	25(OH)2D3	NNP
2056	2059	and	and	CC
2060	2062	RA	RA	NNP
2063	2071	markedly	markedly	RB
2072	2080	enhanced	enhance	VBD
2081	2084	the	the	DT
2085	2091	levels	level	NNS
2092	2094	of	of	IN
2095	2104	p27(KIP1)	p27(kip1)	NN
2105	2115	transcript	transcript	NN
2116	2119	and	and	CC
2120	2127	protein	protein	NN
2128	2130	as	as	IN
2131	2139	compared	compare	VBN
2140	2144	with	with	IN
2145	2151	levels	level	NNS
2152	2159	induced	induce	VBN
2160	2162	by	by	IN
2163	2164	1	1	CD
2164	2165	,	,	,
2166	2175	25(OH)2D3	25(oh)2d3	NN
2176	2181	alone	alone	RB
2181	2182	.	.	.

2183	2185	In	in	IN
2186	2194	addition	addition	NN
2194	2195	,	,	,
2196	2205	exogenous	exogenous	JJ
2206	2215	p27(KIP1)	p27(kip1)	NN
2216	2226	expression	expression	NN
2227	2230	can	can	MD
2231	2238	enhance	enhance	VB
2239	2242	the	the	DT
2243	2248	level	level	NN
2249	2251	of	of	IN
2252	2257	CD11b	CD11b	NNP
2258	2265	antigen	antigen	NN
2266	2268	in	in	IN
2269	2276	myeloid	myeloid	JJ
2277	2285	leukemic	leukemic	JJ
2286	2291	cells	cell	NNS
2291	2292	.	.	.

2293	2295	In	in	IN
2296	2304	contrast	contrast	NN
2304	2305	,	,	,
2306	2308	RA	RA	NNP
2309	2314	alone	alone	RB
2315	2318	can	can	MD
2319	2325	induce	induce	VB
2326	2328	G1	g1	NN
2329	2335	arrest	arrest	NN
2336	2338	of	of	IN
2339	2343	UF-1	uf-1	NN
2344	2349	cells	cell	NNS
2349	2350	;	;	:
2351	2358	however	however	RB
2358	2359	,	,	,
2360	2362	it	it	PRP
2363	2366	did	do	VBD
2367	2370	not	not	RB
2371	2377	result	result	VB
2378	2380	in	in	IN
2381	2383	an	an	DT
2384	2392	increase	increase	NN
2393	2395	of	of	IN
2396	2410	p21(WAF1/CIP1)	p21(WAF1/CIP1)	NNP
2411	2414	and	and	CC
2415	2424	p27(KIP1)	p27(kip1)	NN
2425	2435	transcript	transcript	NN
2436	2439	and	and	CC
2440	2447	protein	protein	NN
2448	2458	expression	expression	NN
2459	2461	in	in	IN
2462	2474	RA-resistant	ra-resistant	JJ
2475	2480	cells	cell	NNS
2480	2481	.	.	.

2482	2487	Taken	take	VBN
2488	2496	together	together	RB
2496	2497	,	,	,
2498	2500	we	we	PRP
2501	2509	conclude	conclude	VBP
2510	2514	that	that	IN
2515	2526	1,25(OH)2D3	1,25(oh)2d3	NN
2527	2534	induces	induce	VBZ
2535	2544	increased	increase	VBN
2545	2555	expression	expression	NN
2556	2558	of	of	IN
2559	2562	cdk	cdk	NN
2563	2573	inhibitors	inhibitor	NNS
2573	2574	,	,	,
2575	2580	which	which	WDT
2581	2589	mediates	mediate	VBZ
2590	2591	a	a	DT
2592	2594	G1	g1	NN
2595	2601	arrest	arrest	NN
2601	2602	,	,	,
2603	2606	and	and	CC
2607	2611	this	this	DT
2612	2615	may	may	MD
2616	2618	be	be	VB
2619	2629	associated	associate	VBN
2630	2634	with	with	IN
2635	2650	differentiation	differentiation	NN
2651	2653	of	of	IN
2654	2666	RA-resistant	ra-resistant	JJ
2667	2671	UF-1	uf-1	NN
2672	2677	cells	cell	NNS
2678	2684	toward	toward	IN
2685	2691	mature	mature	JJ
2692	2704	granulocytes	granulocyte	NNS
2704	2705	.	.	.