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  • Review Article
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Transcription factors in myeloid development: balancing differentiation with transformation

Key Points

  • The formation of myeloid cells is organized by a hierarchical order of self-renewing pluripotent stem cells and transient lineage-affiliated progenitor-cell stages.

  • Myeloid differentiation fate is determined by lineage-specific transcription factors.

  • Selective transcription factors are required for specific developmental steps during myeloid differentiation.

  • Stage-specific functional doses of these transcription factors are tightly controlled at the levels of gene expression, post-transcription and protein–protein interactions.

  • These same transcription factors are frequently disrupted in acute myeloid leukaemia through specific mutation or dysregulation.

  • Genetically engineered mouse models have functionally corroborated the predominant role of transcription factors in the pathogenesis of acute myeloid leukaemia.

  • These transcription factor pathways represent important targets for therapeutic intervention.

Abstract

In recent years, great progress has been made in elucidating the progenitor-cell hierarchy of the myeloid lineage. Transcription factors have been shown to be key determinants in the orchestration of myeloid identity and differentiation fates. Most transcription factors show cell-lineage-restricted and stage-restricted expression patterns, indicating the requirement for tight regulation of their activities. Moreover, if dysregulated or mutated, these transcription factors cause the differentiation block observed in many myeloid leukaemias. Consequently, therapies designed to restore defective transcription factor functions are an attractive option in the treatment of myeloid and other human cancers.

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Figure 1: Current concepts of haematopoietic lineage diversification.
Figure 2: A stepwise requirement for transcription factors during myeloid differentiation.
Figure 3: Regulation of the SPI1 gene locus by a distal element.
Figure 4: model of leukaemia development from blocked myeloid differentiation.

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Acknowledgements

We thank J. Lausen, M. Scheller, S. Ghani, A. Ebralidze and U. Steidl for stimulating discussions and valuable comments on the manuscript, and C. Nerlov for sharing unpublished results. We apologize to all investigators whose work could not be cited owing to space limitations. This work was supported by a Helmholtz Association grant for young investigators and a Lymphoma Research Foundation fellowship to F.R., and US National Institutes of Health grants to D.G.T.

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Glossary

Transcription factors

Specialized nuclear proteins with the ability to bind to DNA. Most transcription factors have transactivation or repressor domains, but in addition they can serve as architectural proteins and induce chromatin remodelling to facilitate the entry of additional activator or repressor complexes.

B-2 cell

A conventional B cell. These cells reside in secondary lymphoid organs and secrete antigen-specific antibodies.

B-1 cell

A cell belonging to the B-cell lineage that mainly populates the peritoneum and secretes polyspecific, low-affinity IgM.

Haploinsufficiency

A gene dosage effect that occurs when a diploid organism requires both functional copies of a gene for a wild-type phenotype. An organism that is heterozygous for a haploinsufficient locus does not have a wild-type phenotype.

DNaseI hypersensitivity sites

Sites of nuclease sensitivity when nuclei from cells are exposed to limiting concentrations of the enzyme deoxyribonuclease I (DNaseI). The digested regions of DNA correspond to sites of open DNA, which might be factor-binding sites or areas of altered nucleosome conformation.

FAB system

The French–American–British classification system of acute myeloid leukaemia (AML) that is based on the assessment of the stage of differentiation of blasts. The subtypes of human AML according to this system are: M0 (undifferentiated), M1 (myeloplastic without maturation), M2 (myeloplastic with maturation), M3 (promyelocytic), M4 (myelomonocytic), M4Eo (myelomonocytic with bone-marrow eosinophilia), M5 (monocytic), M6 (erythroleukaemic) and M7 (megakaryoblastic).

Blast crisis

The terminal phase of chronic myeloid leukaemia, a clonal myeloproliferative disorder of haematopoietic stem cells that typically evolves in three distinct clinical stages: chronic phase, accelerated phase and blast crisis.

FLT3–ITD

A sequence duplication in the juxta-membrane domain of FMS-related tyrosine kinase 3 (FLT3) that is found in 24% of patients with acute myeloid leukaemia. Internal tandem duplication (ITD) mutations result in ligand-independent dimerization and tyrosine autophosphorylation of FLT3.

All-trans retinoic acid

A derivative of vitamin A that is used for the treatment of acute promyelocytic leukaemia (APL, the FAB system subtype M3).

Teratocarcinoma

A malignant germ-cell tumour arising from the ovary or testis that is composed of embryonal carcinoma cells.

Small interfering RNA

Synthetic double-stranded RNA molecules of 19–23 nucleotides, which are used to 'knock down' (silence the expression of) a specific gene. This is known as RNA interference and is mediated by the sequence-specific degradation of mRNA.

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Rosenbauer, F., Tenen, D. Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 7, 105–117 (2007). https://doi.org/10.1038/nri2024

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