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• W2610075594 abstract "•All-trans retinoic acid (ATRA) drives leukemic cells into differentiation and/or apoptosis in a subset of acute myeloid leukemia (AML) patients.•Responsive biomarkers are needed to identify ATRA-susceptible AML patients.•The transcriptional state of leukemia cells determines the susceptibity of the cells to ATRA.•Epigenetic reprogramming might sensitize AML cells to retinoic acid (RA)-based therapy.•RA-based therapies should induce differentiation of leukemic stem cells. The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy. Searching for response biomarkers might also reveal novel RA-based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APL AML patients. Preliminary studies suggest that the epigenetic or transcriptional state of leukemia cells determines their susceptibility to ATRA. We hypothesize that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy. AML relapse is caused by a subpopulation of leukemia cells, named leukemic stem cells (LSCs), which are in a different epigenetic state than the total bulk of the AML. The survival of LSCs after therapy is the main cause of the poor prognosis of AML patients, and novel differentiation therapies should drive these LSCs into maturity. In this review, we summarize the current knowledge on the epigenetic aspects of susceptibility to RA-induced differentiation in APL and non-APL AML. The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy. Searching for response biomarkers might also reveal novel RA-based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APL AML patients. Preliminary studies suggest that the epigenetic or transcriptional state of leukemia cells determines their susceptibility to ATRA. We hypothesize that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy. AML relapse is caused by a subpopulation of leukemia cells, named leukemic stem cells (LSCs), which are in a different epigenetic state than the total bulk of the AML. The survival of LSCs after therapy is the main cause of the poor prognosis of AML patients, and novel differentiation therapies should drive these LSCs into maturity. In this review, we summarize the current knowledge on the epigenetic aspects of susceptibility to RA-induced differentiation in APL and non-APL AML. Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature myeloid cells with abnormal proliferation, differentiation, and survival capacity [1Löwenberg B. Acute myeloid leukemia: The challenge of capturing disease variety.Hematology Am Soc Hematol Educ Program. 2008; 2008: 1-11Crossref Google Scholar, 2Estey E. Döhner H. Acute myeloid leukaemia.Lancet. 2006; 368: 1894-1907Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar]. Different subtypes of AML can be identified based on morphology, immunophenotypic characteristics, cytogenetic aberrations, alterations in gene expression, DNA methylation profiles, and molecular abnormalities [3Walter R.B. Othus M. Burnett A.K. et al.Significance of FAB subclassification of “acute myeloid leukemia” in the 2008 WHO classification: Analysis of 5848 newly diagnosed patients.Blood. 2013; 121: 2424-2431Crossref PubMed Scopus (0) Google Scholar, 4Grimwade D. Mrózek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia.Hematol Oncol Clin North Am. 2011; 25: 1135-1161Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Döhner H. Weisdorf D.J. Bloomfield C.D. Acute myeloid leukemia.N Engl J Med. 2015; 373: 1136-1152Crossref PubMed Scopus (179) Google Scholar, 6Valk P.J. Verhaak R.G. Beijen M.A. et al.Prognostically useful gene-expression profiles in acute myeloid leukemia.N Engl J Med. 2004; 350: 1617-1628Crossref PubMed Scopus (830) Google Scholar, 7Figueroa M.E. Lugthart S. Li Y. et al.DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.Cancer Cell. 2010; 17: 13-27Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar]. Classification based on the integration of karyotype and mutations allows stratification of patients by recurrence risk and survival. For the past 4 decades, treatment of AML with combination chemotherapy consisting of cytosine arabinoside (Ara-C) and an anthracycline (e.g., daunorubicin or idarubicin) has been unchanged. Favorable-risk patients are treated only with chemotherapy, and adverse-risk patients often receive allogenic stem cell transplantation when they have reached a first remission. Despite initial high complete remission rates, the 5-year overall survival rate of adult AML patients is less than 40% [2Estey E. Döhner H. Acute myeloid leukaemia.Lancet. 2006; 368: 1894-1907Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar, 8Khwaja A. Bjorkholm M. Gale R.E. et al.Acute myeloid leukaemia.Nat Rev Dis Primers. 2016; 2: 16010Crossref PubMed Scopus (0) Google Scholar]. This very poor treatment outcome is mainly due to chemotherapy resistance. The only exception is treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) differentiation therapy. Expression of the fusion gene encoding chimeric PML-retinoic acid receptor alpha (RARA) in the leukemic cells of APL patients allows successful application of ATRA [9Warrell R.P. Frankel S.R. Miller W.H. et al.Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid).N Engl J Med. 1991; 324: 1385-1393Crossref PubMed Google Scholar, 10Platzbecker U. Avvisati G. Cicconi L. et al.Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: Final results of the randomized Italian-German APL0406 trial.J Clin Oncol. 2017; 35: 605-612Crossref PubMed Scopus (10) Google Scholar]. ATRA-based therapy has significantly improved long-term clinical outcomes for APL patients and converted this AML subtype from a poor prognostic leukemia to a curable one [11Kakizuka A. Miller W.H. Umesono K. et al.Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.Cell. 1991; 66: 663-674Abstract Full Text PDF PubMed Scopus (1058) Google Scholar, 12Wang Z.Y. Chen Z. Acute promyelocytic leukemia: From highly fatal to highly curable.Blood. 2008; 111: 2505-2515Crossref PubMed Scopus (610) Google Scholar]. Although ATRA-based differentiation therapy is successful in the treatment of APL, its clinical effectiveness in other AML subtypes is limited. Previous preclinical studies have provided evidence that specific molecular abnormalities can unlock ATRA-driven responses in non-APL AML patient cells; that is, AML with aberrant expression of ecotropic viral integration site 1 (EVI-1) [13Verhagen H.J. Smit M.A. Rutten A. et al.Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid.Blood. 2016; 127: 458-463Crossref PubMed Scopus (1) Google Scholar], mutant isocitrate dehydrogenase 1 (IDH1) [14Boutzen H. Saland E. Larrue C. et al.Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia.J Exp Med. 2016; 213: 483-497Crossref PubMed Scopus (0) Google Scholar], mutant nucleophosmin gene (NPM1) [15Schlenk R.F. Lübbert M. Benner A. et al.All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: Results of the randomized AMLSG 07-04 study.Ann Hematol. 2016; 95: 1931-1942Crossref PubMed Scopus (4) Google Scholar, 16Martelli M.P. Gionfriddo I. Mezzasoma F. et al.Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.Blood. 2015; 125: 3455-3465Crossref PubMed Scopus (20) Google Scholar, 17El Hajj H. Dassouki Z. Berthier C. et al.Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells.Blood. 2015; 125: 3447-3454Crossref PubMed Scopus (22) Google Scholar, 18Lu L.F. Boldin M.P. Chaudhry A. et al.Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses.Cell. 2010; 142: 914-929Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar, 19Balusu R. Fiskus W. Rao R. et al.Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1.Blood. 2011; 118: 3096-3106Crossref PubMed Scopus (0) Google Scholar], and AML with an FMS-like tyrosine kinase 3/internal tandem duplication (FLT3-ITD) [20Ma H.S. Greenblatt S.M. Shirley C.M. et al.All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.Blood. 2016; 127: 2867-2878Crossref PubMed Google Scholar]. Together, these studies indicate that a subset of EVI-1-positive, IDH1 mutant, NPM1 mutant, and FLT3-ITD positive AML cases are sensitive for ATRA-induced differentiation (Table 1). Because inhibition of the demethylase LSD1 (also called KDM1A) has been shown to induce susceptibility to ATRA [21Schenk T. Chen W.C. Göllner S. et al.Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia.Nat Med. 2012; 18: 605-611Crossref PubMed Scopus (241) Google Scholar] (Table 2), we hypothesize that AML cells need to have a particular epigenetic and transcriptional state to be susceptible to retinoic acid (RA)-induced differentiation. Therefore, the application of epigenetic-modifying drugs might represent an effective therapeutic strategy for increasing sensitivity to ATRA-induced differentiation. To date, a limited number of preclinical studies have combined epigenetic-modifying drugs with RA-based therapies to test susceptibility to ATRA-induced differentiation in non-APL AML patient samples. Moreover, there is a lack of knowledge of the epigenetic mechanisms underlying ATRA unresponsiveness and of the identity of biomarkers that can predict the response to ATRA. Because the epigenetic state of the leukemic cells might be the key to successful administration of ATRA-based differentiation therapy in non-APL AML, research should focus on elucidation of molecular and epigenetic mechanisms by which susceptibility to ATRA is accomplished [32Petrie K. Zelent A. Waxman S. Differentiation therapy of acute myeloid leukemia: Past, present and future.Curr Opin Hematol. 2009; 16: 84-91Crossref PubMed Scopus (0) Google Scholar]. In this review, we discuss the current understanding of transcriptional and epigenetic regulation involved in mediating ATRA-driven myeloid differentiation responses in APL and non-APL AML subtypes.Table 1Primary human AML with sensitivity to ATRAMolecular aberranciesFrequencyResponse to ATRAEVI-1 positive10–11%Induction of blast differentiation and apoptosis; reduction of leukemic clonogenic capacity in nine of 13 AML cases; reduction of myeloid engraftment in two of three primary EVI-1-positive AML cases 13Verhagen H.J. Smit M.A. Rutten A. et al.Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid.Blood. 2016; 127: 458-463Crossref PubMed Scopus (1) Google ScholarIDH1-R312H mutant6–7%Induction of nuclear lobulation and associated neutrophilic differentiation in eight of 25 samples; induction of granulo-monocytic differentiation in 11 of 25 samples 14Boutzen H. Saland E. Larrue C. et al.Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia.J Exp Med. 2016; 213: 483-497Crossref PubMed Scopus (0) Google ScholarFLT3-ITD positive24%Decreased clonogenic capacity in three of three FLT3-ITD patients' samples; reduced myeloid engraftment in two of two patient samples (first transplantation) 20Ma H.S. Greenblatt S.M. Shirley C.M. et al.All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.Blood. 2016; 127: 2867-2878Crossref PubMed Google ScholarNPM1 mutant30–35%Inhibition of cell growth in four of 11 primary AML samples and induction of apoptosis due to selective proteasomal degradation of mutant NPM1 protein in three of these 11 samples and in one patient harboring the NPM1 mutation without FLT3-ITD 17El Hajj H. Dassouki Z. Berthier C. et al.Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells.Blood. 2015; 125: 3447-3454Crossref PubMed Scopus (22) Google Scholar; ATRA + ATO combination therapy: significant downregulation of NPM1 mutant protein and induction of differentiation, cell-cycle arrest, and apoptosis in two of three patient samples 16Martelli M.P. Gionfriddo I. Mezzasoma F. et al.Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells.Blood. 2015; 125: 3455-3465Crossref PubMed Scopus (20) Google Scholar Open table in a new tab Table 2Preclinical in vitro studies involving combination therapy with ATRA in non-APL AMLPotential combination therapy with ATRACell typeExperimental outcomeCombinations involving molecular aberrancies in AML FLT3-ITD+SorafenibBlasts derived from AML patientsReduction in cell viability of leukemic blasts in vitro; monocytic differentiation, reduction of leukemic cells, and improved survival in mouse AML xenograft models 20Ma H.S. Greenblatt S.M. Shirley C.M. et al.All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.Blood. 2016; 127: 2867-2878Crossref PubMed Google ScholarD-65476MOLM13 and MV4-11 cell linesSignificant increase of antiproliferative activity and induction of apoptosis 22Scholl S. Müller R. Clement J.H. Loncarevic I.F. Böhmer F.D. Höffken K. ATRA can enhance apoptosis that is induced by Flt3 tyrosine kinase inhibition in Flt3-ITD positive cells.Leuk Res. 2006; 30: 633-642Abstract Full Text Full Text PDF PubMed Google ScholarPKC421MOLM13, MOLM14, and MV4-11 cell linesDose-dependent inhibition of cellular proliferation and induction of apoptosis 23Chi H.T. Ly B.T. Vu H.A. Sato Y. Dung P.C. Xinh P.T. Synergistic effect of all-trans retinoic acid in combination with protein kinase C 412 in FMS-like tyrosine kinase 3-mutated acute myeloid leukemia cells.Mol Med Rep. 2015; 11: 3969-3975PubMed Google Scholar NPM1 mutantNSC348884Primary non-APL AML cellsSensitization of ATRA-induced apoptosis in three primary AML patient samples 19Balusu R. Fiskus W. Rao R. et al.Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1.Blood. 2011; 118: 3096-3106Crossref PubMed Scopus (0) Google ScholarCombination with epidrugs LSD inhibitorTCPTEX, KG1a, and HL60 cell lines and primary AML patient samplesIn vitro induction of myeloid differentiation, nuclear lobulation and neutrophilic differentiation, and post-differentiation apoptosis; induction of differentiation-associated formation of granulocytes in primary AML samples; reduced engraftment of primary AML samples in NSG mice; Phase I clinical trial of ATRA-TCP in patients with AML and MDS (NTC02273102) and Phase I/II clinical trial in patients with relapsed or refractory AML (NCT02261779) are currently ongoing 21Schenk T. Chen W.C. Göllner S. et al.Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia.Nat Med. 2012; 18: 605-611Crossref PubMed Scopus (241) Google ScholarKOLC-48 cell lineIncreased cell-cycle arrest and induction of myeloid differentiation in MLL-AF4-positive cells 24Sakamoto K. Imamura T. Yano M. et al.Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARα promoter region.Blood Cancer J. 2014; 4: e205Crossref PubMed Scopus (11) Google Scholar HDAC inhibitorEtinostatKasumi-1 cell line and non-APL AML patient samplesSynergistic effect on differentiation partly due to restored RARB2 expression; ex vivo induction of differentiation and enhanced growth inhibition, but no increase in apoptosis in primary blasts from three of three AML patients 25Blagitko-Dorfs N. Jiang Y. Duque-Afonso J. et al.Epigenetic priming of AML blasts for all-trans retinoic acid-induced differentiation by the HDAC class-I selective inhibitor entinostat.PLoS One. 2013; 8: e75258Crossref PubMed Scopus (11) Google ScholarVPAOCI-AML2 cell line and non-APL AML patient samplesInduction of cell-cycle arrest associated with upregulated p21 expression in vitro; cell-cycle arrest and promotion of apoptosis in four of six primary patient samples 26Trus M.R. Yang L. Suarez Saiz F. Bordeleau L. Jurisica I. Minden M.D. The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells.Leukemia. 2005; 19: 1161-1168Crossref PubMed Scopus (50) Google Scholar; in vivo induction of cell proliferation and differentiation in blasts of seven of eight patients caused by histone H3 and H4 hyperacetylation at the RARA regulatory site 27Cimino G. Lo-Coco F. Fenu S. et al.Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia.Cancer Res. 2006; 66: 8903-8911Crossref PubMed Scopus (0) Google ScholarTSAMOLM14 cell lineInduction of growth inhibition and enhanced differentiation 28Iijima K. Honma Y. Niitsu N. Granulocytic differentiation of leukemic cells with t(9;11)(p22;q23) induced by all-trans-retinoic acid.Leuk Lymphoma. 2004; 45: 1017-1024Crossref PubMed Scopus (8) Google ScholarNon-APL AML patient samplesActivation of myeloid differentiation in leukemic blasts of 23 of 23 patient samples 29Ferrara F.F. Fazi F. Bianchini A. et al.Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia.Cancer Res. 2001; 61: 2-7PubMed Google Scholar DNMT inhibitor5-AzaTHP1 cell lineAdditive induction of myeloid differentiation, inhibition of cell proliferation, and induction of apoptosis compared with ATRA monotherapy 30Fujiki A. Imamura T. Sakamoto K. et al.All-trans retinoic acid combined with 5-Aza-2′-deoxycitidine induces C/EBPα expression and growth inhibition in MLL-AF9-positive leukemic cells.Biochem Biophys Res Commun. 2012; 428: 216-223Crossref PubMed Scopus (3) Google ScholarSN1 and KOCL33 cell linesInduction of growth inhibition and granulocytic differentiation in MLL-rearranged AML cell lines 31Niitsu N. Hayashi Y. Sugita K. Honma Y. Sensitization by 5-aza-2′-deoxycytidine of leukaemia cells with MLL abnormalities to induction of differentiation by all-trans retinoic acid and 1alpha,25-dihydroxyvitamin D3.Br J Haematol. 2001; 112: 315-326Crossref PubMed Scopus (0) Google Scholar Open table in a new tab Retinoids are a class of signaling molecules derived naturally from vitamin A (or retinol) and involved in regulating multiple biological processes, including embryonic development and hematopoietic cell growth and differentiation [33Uray I.P. Dmitrovsky E. Brown P.H. Retinoids and rexinoids in cancer prevention: From laboratory to clinic.Semin Oncol. 2016; 43: 49-64Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 34Samarut E. Rochette-Egly C. Nuclear retinoic acid receptors: Conductors of the retinoic acid symphony during development.Mol Cell Endocrinol. 2012; 348: 348-360Crossref PubMed Scopus (0) Google Scholar]. After uptake by intestinal mucosa cells, dietary-derived retinoids are oxidized into the active compounds retinal and RA, which can then bind to and activate one or more nuclear RA receptors (RARs) and rexinoid receptors (RXRs) to mediate gene expression [34Samarut E. Rochette-Egly C. Nuclear retinoic acid receptors: Conductors of the retinoic acid symphony during development.Mol Cell Endocrinol. 2012; 348: 348-360Crossref PubMed Scopus (0) Google Scholar]. For both the RAR and RXR receptor families, three subtypes—characterized as α, β, and γ—act as ligand-inducible transcription factors that bind predominantly as either homodimers or heterodimers to retinoid acid response elements (RAREs) in the promotor regions of their target genes. In the absence of agonists, complex formation of RXR–RAR heterodimers with nuclear receptor corepressors, including N-CoR, and silencing mediator for retinoid and thyroid hormone receptors actively repress gene transcription via recruitment of histone deacetylases (HDACs) and subsequent chromatin condensation [35Mangelsdorf D.J. Evans R.M. The RXR heterodimers and orphan receptors.Cell. 1995; 83: 841-850Abstract Full Text PDF PubMed Scopus (2561) Google Scholar, 36Kastner P. Mark M. Ghyselinck N. et al.Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development.Development. 1997; 124: 313-326Crossref PubMed Google Scholar, 37Glass C.K. Rosenfeld M.G. The coregulator exchange in transcriptional functions of nuclear receptors.Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar] (Fig. 1A). To date, the endogenous high-affinity ligand of RXR, 9-cis–RA, and the physiological active ligand of RAR, ATRA, are identified as the main activators of RARs. Upon binding of these agonists, conformational changes in the ligand-binding domains of the receptors result in destabilization of the corepressor complex and recruitment of transcriptional coactivators, including histone acetyltransferases (HATs), such as CREB-binding protein (CBP) or p300, and the SRB mediator-containing complex. This leads to transcriptional activation of retinoid target genes through decondensation of the chromatin (Fig. 1A) [37Glass C.K. Rosenfeld M.G. The coregulator exchange in transcriptional functions of nuclear receptors.Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar]. In contrast to RARB, RARA and RARY are widely expressed in hematopoietic cells, including myeloid cells [38Purton L.E. Dworkin S. Olsen G.H. et al.RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.J Exp Med. 2006; 203: 1283-1293Crossref PubMed Scopus (0) Google Scholar]. Several in vitro and in vivo studies have focused on the effect of knocking out RARA or RARY in normal hematopoietic cells. Although hematopoietic stem cells (HSCs) highly express RARA, its disruption does not cause abnormalities in hematopoiesis [39Ricote M. Snyder C.S. Leung H.Y. Chen J. Chien K.R. Glass C.K. Normal hematopoiesis after conditional targeting of RXR in murine hematopoietic stem/progenitor cells.J Leukoc Biol. 2006; 80: 850-861Crossref PubMed Scopus (0) Google Scholar]. Conversely, mice deficient in RARY showed reduced HSCs, significantly increased granulocyte/macrophage progenitors and granulocytes in the bone marrow, peripheral blood, and spleen, and developed a myeloproliferative syndrome (MPS) [38Purton L.E. Dworkin S. Olsen G.H. et al.RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.J Exp Med. 2006; 203: 1283-1293Crossref PubMed Scopus (0) Google Scholar, 40Walkley C.R. Olsen G.H. Dworkin S. et al.A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency.Cell. 2007; 129: 1097-1110Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. This development of MPS was not hematopoietic cell intrinsic but caused by loss of RARY in the microenvironment, suggesting a function of niche-expressed RARY in regulating the balance between HSC proliferation, differentiation, and self-renewal [40Walkley C.R. Olsen G.H. Dworkin S. et al.A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor γ deficiency.Cell. 2007; 129: 1097-1110Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The enhanced repopulation potential of HSCs after ATRA treatment might also be regulated via niche-expressed RARY [38Purton L.E. Dworkin S. Olsen G.H. et al.RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.J Exp Med. 2006; 203: 1283-1293Crossref PubMed Scopus (0) Google Scholar]. HSCs that are dissociated from their microenvironment undergo differentiation. However, inhibition of RA signaling maintained their primitive phenotype and function, suggesting that HSCs are intrinsically programmed to undergo RA-mediated differentiation unless prevented from doing so by the bone marrow niche [41Ghiaur G. Yegnasubramanian S. Perkins B. Gucwa J.L. Gerber J.M. Jones R.J. Regulation of human hematopoietic stem cell self-renewal by the microenvironment's control of retinoic acid signaling.Proc Natl Acad Sci U S A. 2013; 110: 16121-16126Crossref PubMed Scopus (38) Google Scholar]. These knockout studies indicate that RAR activity is regulated differentially during various stages of normal hematopoiesis and that ATRA treatment can enhance HSC self-renewal capacity. The role of retinoids in cancer has been studied predominantly in APL. APL, defined by the French–American–British classification as the M3 subtype of AML [42Bennett J.M. Catovsky D. Daniel M.T. et al.Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group.Ann Intern Med. 1985; 103: 620-625Crossref PubMed Google Scholar], accounts for 10% of adult AML patients and is characterized by a differentiation arrest at the promyelocytic stage. APL is associated with the presence of a specific chromosomal translocation involving the RARA gene on chromosome 17 and the promyelocytic leukemia (PML) gene on chromosome 15 [11Kakizuka A. Miller W.H. Umesono K. et al.Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.Cell. 1991; 66: 663-674Abstract Full Text PDF PubMed Scopus (1058) Google Scholar, 43de Thé H. Lavau C. Marchio A. Chomienne C. Degos L. Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.Cell. 1991; 66: 675-684Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 44Grignani F. Ferrucci P.F. Testa U. et al.The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells.Cell. 1993; 74: 423-431Abstract Full Text PDF PubMed Scopus (0) Google Scholar]. In the 1980s, several studies demonstrated that leukemic cell lines and primary APL cells could effectively undergo granulocytic differentiation in response to ATRA [45Breitman T.R. Selonick S.E. Collins S.J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.Proc Natl Acad Sci U S A. 1980; 77: 2936-2940Crossref PubMed Google Scholar, 46Breitman T.R. Collins S.J. Keene B.R. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid.Blood. 1981; 57: 1000-1004Crossref PubMed Google Scholar]. A pharmacological dose of ATRA overcomes the PML–RARA-mediated differentiation block and restores RA target gene transcription and differentiation. In a follow-up to these studies, a clinical trial showed that ATRA induces complete remission in the majority of APL patients [47Huang M.E. Ye Y.C. Chen S.R. et al.Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia.Blood. 1988; 72: 567-572Crossref PubMed Google Scholar]. Subsequently, the use of combinations of ATRA with anthracycline-based chemotherapy or arsenic trioxide (ATO), which induces PML–RARA degradation, oxidative stress, differentiation, and apoptosis of APL blasts [48Jeanne M. Lallemand-Breitenbach V. Ferhi O. et al.PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.Cancer Cell. 2010; 18: 88-98Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 49Lang E. Grudic A. Pankiv S. et al.The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycl" @default.
• W2610075594 created "2017-05-05" @default.
• W2610075594 creator A5050161269 @default.
• W2610075594 creator A5076242051 @default.
• W2610075594 creator A5090161229 @default.
• W2610075594 date "2017-08-01" @default.
• W2610075594 modified "2023-10-17" @default.
• W2610075594 title "Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation" @default.
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