Hartmut Geiger

Haematologica

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haematologica | 2017; 102(12)EDITORIALS1969Balance your folate or the yin and yang of folate in hematopoiesisHartmut GeigerInstitute of Molecular Medicine and Aging Research Center, University of Ulm, Germany and Division of Experimental Hematology andCancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USAE-mail: hartmut.geiger@uni-ulm.de / hartmut.geiger@cchmc.orgdoi:10.3324/haematol.2017.179838Anew study in mice demonstrates that, in general, bothlow and high levels of dietary folate compromisehematopoiesis, and affect the B-cell progenitor com-partment in particular.1 Given that there are substantial frac-tions of the world population at risk for either excessive (viafortified diets) or very low folate intake, this study might con-tribute to novel public policy recommendations on the level offolate intake, specifically in the context of fortified diets. There has, of late, been a widespread interest in the role ofdietary nutrients in hematopoiesis, including specific typesof vitamins and amino acids, as, interestingly, dietary factorsseem to play a critical regulatory role in blood cell produc-tion as well as in leukemia. For example, high-dose vitaminC treatment induced hematopoietic stem cells (HSCs) tomature, and suppressed the growth of Tet methylcytosinedioxygenase 2 (Tet2) deficient leukemia cancer stem cellsfrom human patients implanted in mice, by promoting DNAmethylation.2 It was further demonstrated that in theabsence of retinoic acid, a vitamin A metabolite, active HSCsare unable to return to a dormant state, instead maturinginto specialized blood cells, and that mice fed with a vitaminA-deficient diet showed a disrupted reentry of HSCs intodormancy following exposure to inflammatory stress stim-uli, thus eventually losing their HSCs.3 The Nakauchi labora-tory showed that a diet deficient in the essential amino acidvaline, resulted in the selective depletion of HSCs in thebone marrow of mice, which allowed for a successful trans-plant of HSCs without an additional preconditioning regi-men.4 Ultimately, it has also been reported that multiplecycles of short-term fasting, and the accompanying restrict-ed uptake of vitamins and essential amino acids, leads to sig-nal transduction changes in HSCs and niche cells which pro-mote stress resistance, self-renewal, and regeneration.5We can now add to this list a novel yin/yang role of folatein hematopoiesis. Folate is a water-soluble B vitamin (coen-zyme) listed as vitamin B9. Generally, folate coenzymes,such as vitamin B9 and vitamin B12, act as acceptors anddonors of one-carbon units in a variety of reactions critical tonucleic acids synthesis (including thymine, but also purinebases), amino acids and DNA methylation reactions, andhence epigenetic mechanisms.6 An inadequate low folatestatus during early pregnancy increases the risk of congenitalabnormalities. Notably, neural tube defects have been linkedto inadequate levels of folate provided to the fetus in the firsttrimester of development. In general, due to the molecularrole of folate in nucleotide synthesis, systems with an overallhigh number of dividing cells, such as the hematopoietic sys-tem, depend on proper levels of folate intake to provide ade-quate levels of erythrocytes and leukocytes and to preventanemia.7 Erythroblasts, for example, require folate for prolif-eration during their differentiation. Folate further supportsthe generation of “normal” red blood cells in sickle cellpatients.8 The negative role of low folate levels with regardto hematopoiesis has therefore been recognized for quitesome time.7,9Folate is provided naturally by a whole variety of foods,including green leafy vegetables as well as meat, fish, eggsand grains. Folate can also be chemically synthesized. Due tothe low dietary intake of folate in multiple countries, and itsvital role in preventing multiple congenital defects, folate hasbeen supplemented in at least one major cereal grain productsince the late 1990s in order to reduce, for instance, neuraltube defects (which it proved to do) in more than 70 coun-tries worldwide, including North America, while in the EUsuch a fortification with folate is not mandatory.In contrast to the well-known positive benefits of folatesupplementation, epidemiological data also support a likelynegative impact of high levels of folate intake with respectto diseases and cancer;10 thus, both too low and very highlevels of folate in diets might have negative consequenceson health. While there are ample experimental studies onthe negative consequences of low levels of dietary folateintake, the impact of high levels of folate has not of yet beenaddressed in great detail.  The toxicity of folic acid has, upto now, been universally regarded as being very low, asfolate is a water-soluble vitamin and thus an excess will belikely removed from the body through urine, as in the caseof vitamin C. Henry et al. have now addressed, in an elegantset of well designed experiments, the extent to which dis-tinct levels of dietary folate influence B cell developmentand hematopoiesis, via transplantation experiments in par-ticular.1 To this end, they simply fed mice diets deficient infolate or diets that contained high levels of folate for up to12 months. The diet high in folate resulted in folate serumlevels that are within the range which are likewise achievedwith fortified diets in human serum. Both low and high lev-els of folate resulted in impaired hematopoiesis, and prima-rily affected the B cell compartment. High and low levels offolate further reduced the survival rate of animals exposedto an irradiation dose that was not lethal to control animals.These novel studies ultimately confirm that excessively lowand high levels of dietary folic acid negatively impact B celldevelopment and hematopoiesis.  Interestingly, changes infolate primarily affected the nucleotide synthesis pathwayin hematopoietic cells, while other pathways linked tofolate seemed to play only a minor role in affectinghematopoiesis. This suggests that hematopoietic cells mightbe very sensitive to changes in the level of nucleotides, bothtoo low and too high. This work, although inherently lessmechanistic than, for example, pure “genetic” approaches, isnonetheless an important contribution to the field of dietaryinterventions in hematopoiesis and their influence onmetabolites in the system. These results will need to be fur-ther tested in additional epidemiological studies, focusingon the high or higher end levels of folate and their con-nection to the long-term outcome rather than investigat-ing low levels and their connection to disease. Takentogether, these data will support the consideration ofnovel public guidelines on the recommended level offolate that will keep one healthy and strong.References1. Henry C, Nemkov T, Casás-Selves M, et al. Folate dietary insuffi-ciency and folic acid supplementation similarly impair metabolismand compromise hematopoiesis. Haematologica 2017;102(12):1985-1994.2. Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 functionblocks aberrant self-renewal and leukemia progression. Cell.2017;170(6):1079-1095.e20.3. Cabezas-Wallscheid N, Buettner F, Sommerkamp P, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy.Cell. 2017;169(5):807-823.e19.4. Taya Y, Ota Y, Wilkinson AC, et al. Depleting dietary valine permitsnonmyeloablative mouse hematopoietic stem cell transplantation.Science. 2016;354(6316):1152-1155.5. Cheng CW, Adams GB, Perin L, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration andreverse immunosuppression. Cell Stem Cell. 2014;14(6):810-823.6. Yang M, Vousden KH. Serine and one-carbon metabolism in cancer.Nat Rev Cancer. 2016;16(10):650-662.7. Bills ND, Koury MJ, Clifford AJ, Dessypris EN. Ineffectivehematopoiesis in folate-deficient mice. Blood. 1992;79(9):2273-2280.8. Koury MJ, Ponka P. New insights into erythropoiesis: the roles offolate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105-131.9. Salojin KV, Cabrera RM, Sun W, et al. A mouse model of hereditaryfolate malabsorption: deletion of the PCFT gene leads to systemicfolate deficiency. Blood. 2011;117(18):4895-4904.10. Rycyna KJ, Bacich DJ, O'Keefe DS. Opposing roles of folate inprostate cancer. Urology. 2013;82(6):1197-1203.Editorials1970 haematologica | 2017; 102(12)Transplantation for therapy-related, TP53-mutated myelodysplastic syndrome – not because we can, but because we shouldCorey CutlerDana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAE-mail: corey_cutler@dfci.harvard.edudoi:10.3324/haematol.2017.181180To the man who only has a hammer, everything he encountersbegins to look like a nail.Abraham Maslow, and others Transplant physicians have often been accused ofperforming allogeneic hematopoietic stem celltransplant (HSCT) in patients for whom no hope ofcure, or even meaningful gain, was thought plausible, sim-ply because HSCT was deemed possible. Exemplifyingthis is the concept of transplantation for therapy-relatedmyelodysplastic syndrome (tMDS), or MDS associatedwith the most severe of genetic lesions, TP53, for whichoutcomes have historically been poor.In this issue of Haematologica, Aldoss and colleaguesfrom the City of Hope Medical Center compare the out-comes of patients with tMDS and de novo MDS whounderwent allogeneic HSCT, and correlate molecular fea-tures with outcome.1 Although the study was limited bysmall sample size, the authors noted no significant differ-ences in all important post-HSCT clinical outcomes,including survival, between tMDS and de novo MDSpatients, even when prior chemoradiotherapy was con-sidered in multivariable models. This analysis thereforesuggests that allogeneic transplantation for tMDS shouldbe performed whenever it would be considered in the denovo MDS setting.Perhaps even more importantly, the authors examinethe impact of molecular lesions on transplant outcome ina subset of the patients. From the original cohort, 60tMDS patients underwent a comprehensive molecularanalysis: 30% had a TP53 mutation, and the authorsfound that the presence or absence of a TP53 mutationhad no correlation with outcome among these tMDSpatients, although sample sizes were limited. In this con-text, grouping a heterogeneous subset of patients withgenetic changes associated with adverse outcome in thenon-transplant setting did carry prognostic information.In patients with any one of five genes (TP53, EZH2,ETV6, RUNX1, ASXL1) associated with adverse risk(48% of molecularly characterized tMDS patients) theauthors demonstrated an adverse impact on relapse-freesurvival (hazard ratio: 1.58). This difference was also notstatistically significant due to small sample size. It isworth noting that in this single center, retrospectiveanalysis, outcomes were generally favorable, with 5-yearoverall survival rates approaching 50%.  Numerous studies have now examined the outcomesassociated with molecular mutations following allogeneicHSCT (Table 1); however, this is one of the largest tospecifically examine tMDS patients and compare theiroutcomes with those of patients with de novo MDS.Initial studies examining molecular prognostic featuresdemonstrated dismal results for patients with mutatedTP53.2 In a study of 87 MDS patients who underwentallogeneic HSCT at our institute, there were no long-termsurvivors in the subset with TP53 mutations, with themajority of deaths occurring within the first 12 monthsfollowing allogeneic HSCT. Fifteen of 18 deaths in thisgroup were attributed to disease relapse. While samplesizes were exceedingly small, this result instantlychanged the landscape of transplantation, with manycenters deciding not to perform HSCT in TP53-mutatedMDS patients at all. Other larger series have now reported outcomes ofTP53-mutated HSCT patients with slightly more promis-ing results. For example, Yoshizato and colleagues

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