The hematopoietic system consists of well-characterized lineages that provide a diverse repertoire of cell subsets and highly specialized immune functions. This review summarizes the key characteristics and criteria that define hematopoietic cell fate conversion. Perturbation of lineage-specific transcription factors can enable cell fate reprogramming through transdifferentiation, dedifferentiation, or lineage diversion. Members of the CCAAT/enhancer binding protein family of transcription factors, which efficiently convert B cells into macrophages and neutrophils, serve here as a prime example for illustrating the underlying molecular processes. In addition, this review explores disease-associated phenomena, such as lineage infidelity in leukemia, and highlights novel therapeutic strategies that employ fate conversion. Controlled reprogramming systems can also serve as scalable and robust in vitro platforms for screening approaches and for dissecting functional mechanisms. Thus, hematopoietic cell fate reprogramming provides valuable insights into the specification of cellular identity and offers translational opportunities in immunity and cancer.
AdolfssonJ, ManssonR, Buza-VidasN, et al.Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell2005;121(2):295–306.
2.
AkasakaT, BalasasT, RussellLJ, et al.Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood2007;109(8):3451–3461.
3.
Alquicira-HernandezJ, PowellJE, PhanTG. No evidence that plasmablasts transdifferentiate into developing neutrophils in severe COVID-19 disease. Clin Transl Immunology2021;10(7):e1308.
4.
AndreevaL, HillerB, KostrewaD, et al.cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature2017;549(7672):394–398.
5.
ArnanC, UllrichS, Pulido-QuetglasC, et al.Paired guide RNA CRISPR-Cas9 screening for protein-coding genes and lncRNAs involved in transdifferentiation of human B-cells to macrophages. BMC Genomics2022;23(1):402.
6.
AscicE, AkerstromF, Sreekumar NairM, et al.In vivo dendritic cell reprogramming for cancer immunotherapy. Science2024;386(6719):eadn9083.
7.
BaaschS, GiansantiP, KolterJ, et al.Cytomegalovirus subverts macrophage identity. Cell2021;184(14):3774–3793.e3725.
8.
Barneda-ZahoneroB, Roman-GonzalezL, CollazoO, et al.HDAC7 is a repressor of myeloid genes whose downregulation is required for transdifferentiation of pre-B cells into macrophages. PLoS Genet2013;9(5):e1003503.
9.
BarozziI, SimonattoM, BonifacioS, et al.Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol Cell2014;54(5):844–857.
10.
BlauHM, ChiuCP, WebsterC. Cytoplasmic activation of human nuclear genes in stable heterocaryons. Cell1983;32(4):1171–1180.
11.
BlauHM, PavlathGK, HardemanEC, et al.Plasticity of the differentiated state. Science1985;230(4727):758–766.
12.
BussmannLH, SchubertA, Vu ManhTP, et al.A robust and highly efficient immune cell reprogramming system. Cell Stem Cell2009;5(5):554–566.
13.
CarottaS, DakicA, D’AmicoA, et al.The transcription factor PU.1 controls dendritic cell development and Flt3 cytokine receptor expression in a dose-dependent manner. Immunity2010;32(5):628–641.
14.
CedarH, BergmanY. Epigenetics of haematopoietic cell development. Nat Rev Immunol2011;11(7):478–488.
15.
CerneckisJ, CaiH, ShiY. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Signal Transduct Target Ther2024;9(1):112.
16.
ChapiroE, RussellL, Radford-WeissI, et al.Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia. Blood2006;108(10):3560–3563.
17.
ChenC, ParkB, RagonnaudE, et al.Cancer co-opts differentiation of B-cell precursors into macrophage-like cells. Nat Commun2022;13(1):5376.
18.
CirovicB, de BreeLCJ, GrohL, et al.BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment. Cell Host Microbe2020;28(2):322–334.e325.
19.
CirovicB, SchonheitJ, Kowenz-LeutzE, et al.C/EBP-induced transdifferentiation reveals granulocyte-macrophage precursor-like plasticity of B cells. Stem Cell Reports2017;8(2):346–359.
20.
CobaledaC, BusslingerM. Developmental plasticity of lymphocytes. Curr Opin Immunol2008;20(2):139–148.
21.
DavisRL, WeintraubH, LassarAB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell1987;51(6):987–1000.
22.
de LavalB, MaurizioJ, KandallaPK, et al.C/EBPbeta-dependent epigenetic memory induces trained immunity in hematopoietic stem cells. Cell Stem Cell2020;26(5):657–674.e658.
23.
Di TullioA, Vu ManhTP, SchubertA, et al.CCAAT/enhancer binding protein alpha (C/EBP(alpha))-induced transdifferentiation of pre-B cells into macrophages involves no overt retrodifferentiation. Proc Natl Acad Sci U S A2011;108(41):17016–17021.
24.
EW, FeiL, WangJ, et al.Dynamics of cell fate decisions during chemically induced multi-lineage trans-differentiation at single-cell level. Adv Sci (Weinh)2025;12(17):e2409642.
25.
FeldmanAL, ArberDA, PittalugaS, et al.Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: Evidence for transdifferentiation of the follicular lymphoma clone. Blood2008;111(12):5433–5439.
26.
FraserCR, WangW, GomezM, et al.Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma to interdigitating dendritic cell sarcoma: Evidence for transdifferentiation of the lymphoma clone. Am J Clin Pathol2009;132(6):928–939.
27.
FukuchiY, ShibataF, ItoM, et al.Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBP alpha. Embo J2006;25(14):3398–3410.
28.
GaidtMM, EbertTS, ChauhanD, et al.Human monocytes engage an alternative inflammasome pathway. Immunity2016;44(4):833–846.
29.
GaidtMM, EbertTS, ChauhanD, et al.The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell2017;171(5):1110–1124.e18; doi: 10.1016/j.cell.2017.09.039
30.
GardnerR, WuD, CherianS, et al.Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood2016;127(20):2406–2410.
31.
GrafT. Historical origins of transdifferentiation and reprogramming. Cell Stem Cell2011;9(6):504–516.
32.
GuilliamsM, MildnerA, YonaS. Developmental and functional heterogeneity of monocytes. Immunity2018;49(4):595–613.
33.
GurdonJB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol1962;10:622–640.
34.
HanahanD. Hallmarks of cancer: New dimensions. Cancer Discov2022;12(1):31–46.
35.
HeathV, SuhHC, HolmanM, et al.C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo. Blood2004;104(6):1639–1647.
36.
Henriques-OliveiraL, AltmanAR, KurochkinI, et al.Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity. Immunity2025;58(10):2419–2438.e2413.
37.
HersbachBA, FischerDS, MasserdottiG, et al.Probing cell identity hierarchies by fate titration and collision during direct reprogramming. Mol Syst Biol2022;18(9):e11129.
38.
HsuCL, King-FleischmanAG, LaiAY, et al.Antagonistic effect of CCAAT enhancer-binding protein-alpha and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors. Proc Natl Acad Sci U S A2006;103(3):672–677.
39.
HuT, MurdaughR, NakadaD. Transcriptional and microenvironmental regulation of lineage ambiguity in leukemia. Front Oncol2017;7:268.
40.
HuangME, YeYC, ChenSR, et al.Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood1988;72(2):567–572.
41.
HuangS. The molecular and mathematical basis of Waddington’s epigenetic landscape: A framework for post-Darwinian biology? Bioessays2012;34(2):149–157.
42.
IwasakiH, AkashiK. Myeloid lineage commitment from the hematopoietic stem cell. Immunity2007;26(6):726–740.
43.
IwasakiH, MizunoS, ArinobuY, et al.The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev2006;20(21):3010–3021.
44.
IwasakiH, MizunoS, WellsRA, et al.GATA-1 converts lymphoid and myelomonocytic progenitors into the megakaryocyte/erythrocyte lineages. Immunity2003;19(3):451–462.
45.
Iwasaki-AraiJ, IwasakiH, MiyamotoT, et al.Enforced granulocyte/macrophage colony-stimulating factor signals do not support lymphopoiesis, but instruct lymphoid to myelomonocytic lineage conversion. J Exp Med2003;197(10):1311–1322.
46.
JacobsenSEW, NerlovC. Haematopoiesis in the era of advanced single-cell technologies. Nat Cell Biol2019;21(1):2–8.
47.
JoungJ, MaS, TayT, et al.A transcription factor atlas of directed differentiation. Cell2023;186(1):209–229.e226.
48.
JungS, AppletonE, AliM, et al.A computer-guided design tool to increase the efficiency of cellular conversions. Nat Commun2021;12(1):1659.
49.
KaufmannE, SanzJ, DunnJL, et al.BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell2018;172(1–2):176–190.e119.
50.
KawanoY, KatsuyaN, MoriyamaM, et al.IL-6-C/EBPbeta signaling drives monocytic differentiation of murine cultured lymphoid progenitors with immunoregulatory properties. Cell Death Dis2025;16(1):612.
51.
KingAG, KondoM, SchererDC, et al.Lineage infidelity in myeloid cells with TCR gene rearrangement: A latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling. Proc Natl Acad Sci U S A2002;99(7):4508–4513.
52.
KondoM, SchererDC, MiyamotoT, et al.Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature2000;407(6802):383–386.
53.
KulessaH, FramptonJ, GrafT. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev1995;9(10):1250–1262.
54.
KurochkinI, AltmanAR, CaiadoI, et al.A combinatorial transcription factor screening platform for immune cell reprogramming. Cell Syst2026;17(1):101457; doi: 10.1016/j.cels.2025.101457
55.
LaiosaCV, StadtfeldM, XieH, et al.Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP alpha and PU.1 transcription factors. Immunity2006;25(5):731–744.
56.
LambertSA, JolmaA, CampitelliLF, et al.The human transcription factors. Cell2018;172(4):650–665.
57.
LamprechtB, WalterK, KreherS, et al.Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med2010;16(5):571–579, 1p following 579.
58.
LaurentiE, GottgensB. From haematopoietic stem cells to complex differentiation landscapes. Nature2018;553(7689):418–426.
59.
LiP, BurkeS, WangJ, et al.Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science2010;329(5987):85–89.
60.
LindeMH, FanAC, KohnkeT, et al.Reprogramming cancer into antigen-presenting cells as a novel immunotherapy. Cancer Discov2023;13(5):1164–1185.
61.
LiuY, YuC, DaleyTP, et al.CRISPR activation screens systematically identify factors that drive neuronal fate and reprogramming. Cell Stem Cell2018;23(5):758–771.e758.
62.
MansfieldPK, MehrmalS, HurleyMY, et al.Diffuse large B-cell lymphoma transdifferentiating into histiocytic sarcoma: Case report + systematic review. J Cutan Pathol2026;53(4):362–369; doi: 10.1111/cup.70051
63.
McClellanJS, DoveC, GentlesAJ, et al.Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages. Proc Natl Acad Sci U S A2015;112(13):4074–4079.
NagaiY, GarrettKP, OhtaS, et al.Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity2006;24(6):801–812.
66.
NechanitzkyR, AkbasD, SchererS, et al.Transcription factor EBF1 is essential for the maintenance of B cell identity and prevention of alternative fates in committed cells. Nat Immunol2013;14(8):867–875.
67.
NerlovC. The C/EBP family of transcription factors: A paradigm for interaction between gene expression and proliferation control. Trends Cell Biol2007;17(7):318–324.
68.
NowakD, StewartD, KoefflerHP. Differentiation therapy of leukemia: 3 decades of development. Blood2009;113(16):3655–3665.
69.
NuttSL, HeaveyB, RolinkAG, et al.Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature1999;401(6753):556–562.
70.
PabstT, MuellerBU. Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin Cancer Res2009;15(17):5303–5307.
71.
PabstT, MuellerBU, ZhangP, et al.Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet2001;27(3):263–270.
72.
PevnyL, SimonMC, RobertsonE, et al.Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature1991;349(6306):257–260.
73.
PiresCF, RosaFF, KurochkinI, et al.Understanding and modulating immunity with cell reprogramming. Front Immunol2019;10:2809.
74.
RackhamOJ, FirasJ, FangH, et al.A predictive computational framework for direct reprogramming between human cell types. Nat Genet2016;48(3):331–335.
75.
RapinoF, RoblesEF, Richter-LarreaJA, et al.C/EBPalpha induces highly efficient macrophage transdifferentiation of B lymphoma and leukemia cell lines and impairs their tumorigenicity. Cell Rep2013;3(4):1153–1163.
76.
Rodriguez-UbrevaJ, CiudadL, Gomez-CabreroD, et al.Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes. Nucleic Acids Res2012;40(5):1954–1968.
77.
Rodriguez-UbrevaJ, CiudadL, van OevelenC, et al.C/EBPa-mediated activation of microRNAs 34a and 223 inhibits Lef1 expression to achieve efficient reprogramming into macrophages. Mol Cell Biol2014;34(6):1145–1157.
78.
RolinkAG, NuttSL, MelchersF, et al.Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell progenitors. Nature1999;401(6753):603–606.
79.
RosaFF, PiresCF, KurochkinI, et al.Direct reprogramming of fibroblasts into antigen-presenting dendritic cells. Sci Immunol2018;3(30):eaau4292.
80.
RosaFF, PiresCF, KurochkinI, et al.Single-cell transcriptional profiling informs efficient reprogramming of human somatic cells to cross-presenting dendritic cells. Sci Immunol2022;7(69):eabg5539.
81.
SadriaM, BuryTM. FateNet: An integration of dynamical systems and deep learning for cell fate prediction. Bioinformatics2024;40(9):btae525.
82.
SchanielC, GottarM, RoosnekE, et al.Extensive in vivo self-renewal, long-term reconstitution capacity, and hematopoietic multipotency of Pax5-deficient precursor B-cell clones. Blood2002;99(8):2760–2766.
83.
SilbertSK, RankinAW, HoangCN, et al.Project EVOLVE: An international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia. Blood. Epub Ahead of Print2025;146(4):437–455; doi: 10.1182/blood.2024026655
84.
SlamovaL, StarkovaJ, FronkovaE, et al.CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage. Leukemia2014;28(3):609–620.
85.
SomasundaramR, AhsbergJ, OkuyamaK, et al.Clonal conversion of B lymphoid leukemia reveals cross-lineage transfer of malignant states. Genes Dev2016;30(22):2486–2499.
86.
StikG, VidalE, BarreroM, et al.CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response. Nat Genet2020;52(7):655–661.
87.
SwannJW, OlsonOC, PassegueE. Made to order: Emergency myelopoiesis and demand-adapted innate immune cell production. Nat Rev Immunol2024;24(8):596–613.
88.
TaghonT, YuiMA, RothenbergEV. Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat Immunol2007;8(8):845–855.
89.
TakahashiK, YamanakaS. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell2006;126(4):663–676.
90.
TakahashiK, YamanakaS. A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol2016;17(3):183–193.
91.
TakahashiK, TanabeK, OhnukiM, et al.Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell2007;131(5):861–872.
92.
TapscottSJ, DavisRL, ThayerMJ, et al.MyoD1: A nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science1988;242(4877):405–411.
93.
Torcal GarciaG, Kowenz-LeutzE, TianTV, et al.Carm1-arginine methylation of the transcription factor C/EBPalpha regulates transdifferentiation velocity. Elife2023;12:e83951.
94.
TsukadaJ, YoshidaY, KominatoY, et al.The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine2011;54(1):6–19.
95.
van OevelenC, CollombetS, VicentG, et al.C/EBPalpha activates pre-existing and de novo macrophage enhancers during induced pre-B cell transdifferentiation and myelopoiesis. Stem Cell Reports2015;5(2):232–247.
96.
WangH, YangY, LiuJ, et al.Direct cell reprogramming: Approaches, mechanisms and progress. Nat Rev Mol Cell Biol2021;22(6):410–424.
97.
WangJ, SunS, DengH. Chemical reprogramming for cell fate manipulation: Methods, applications, and perspectives. Cell Stem Cell2023;30(9):1130–1147; doi: 10.1016/j.stem.2023.08.001
98.
WilkAJ, RustagiA, ZhaoNQ, et al.A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med2020;26(7):1070–1076.
99.
WilmutI, SchniekeAE, McWhirJ, et al.Viable offspring derived from fetal and adult mammalian cells. Nature1997;385(6619):810–813.
100.
XieH, YeM, FengR, et al.Stepwise reprogramming of B cells into macrophages. Cell2004;117(5):663–676.
101.
XiuY, DongQ, FuL, et al.Coactivation of NF-kappaB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion. Blood2020;135(2):108–120.
102.
YeB, YangL, LiuB, et al.Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity. Cell Mol Immunol2022;19(5):619–633.
103.
ZhangDE, ZhangP, WangND, et al.Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A1997;94(2):569–574.
104.
ZhangM, DongY, HuF, et al.Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes. Nat Immunol2018;19(9):1036; doi: 10.1038/s41590-018-0046-x
105.
ZimmermannovaO, FerreiraAG, AscicE, et al.Restoring tumor immunogenicity with dendritic cell reprogramming. Sci Immunol2023;8(85):eadd4817.
