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The first two decades of the 21st century have shown major breakthroughs in the development of protocols for generating human hematopoietic cells ex vivo and for engineering them genetically. These breakthroughs have come from the discovery that immortal lines of pluripotent cells, very similar to embryonic stem cells and capable of generating cells of all tissues, can be readily derived from many types of mature human cells. Also significant has been the development of strategies for targeting genetic changes in genomic DNA with unprecedented specificity and efficiency. These findings make it possible to analyze and manipulate previously inaccessible stages of human tissue development and human disease processes. These capabilities have also sparked the pursuit of new systems for testing novel treatments that were recently seen as “pipe dreams.” Together, the promise afforded these initial, but seminal, advances has changed our appreciation of the future landscape of general regenerative medicine and for hematologic diseases in particular.

Acronyms and Abbreviations

BCL-XL - B-cell lymphoma-extra large protein encoded by a BCL2-like gene; BMP-bone morphogenic protein; CFC-colony forming cell; CML-chronic myeloid leukemia; CRISPR-clustered regularly interspaced short palindromic repeats; EB-embryoid body; EpiSC-epiblast stem cell; ESC-embryonic stem cell; FACS-fluorescence-activated cell sorting; FGF-fibroblast growth factor; GMP-good manufacturing process; GSK3β-glycogen synthase kinase-3β; HSC-hematopoietic stem cell; ICM-inner cell mass; iPSC-induced pluripotent stem cell; LIF-leukemia inhibitory factor; MHC-major histocompatibility class; MEF-murine embryonic fibroblast; MET-mesenchymal to epithelial transition; NK-natural killer; NSG-RC-NOD/scid/IL2Rγchain-null mouse-repopulating cell; RBC-red blood cell; SCF-stem cell factor; Flt3L-flt3-ligand; TALEN-transcription activator-like effector nuclease; TCR-T-cell receptor; TIL-tumor-infiltrating lymphocyte; TPO-thrombopoietin.

One of the first major breakthroughs in the field of regenerative medicine in general, and hematology in particular, was the discovery that the differentiation state of an adult human somatic cell is reversible. Many differentiated cell types can be efficiently and rapidly returned to that of a human embryonic stem cell (ESC) state, by transducing the cells with a combination of four genes.1 The ESC-like cells obtained are referred to as induced pluripotent stem cells (iPSCs) to reflect their method of creation. The establishment of standard protocols that produce this reversion, the introduction of defined media for the cells’ propagation, and reduced ethical concerns with their origin by comparison to ESCs,2 have made iPSCs desired for many studies. iPSCs are used to analyze the genesis and developmental progression of human hematopoietic cells, to create a potentially unlimited supply of functionally competent mature blood cells, and to produce new human disease models.3–5 The discovery that a differentiated cell can be reverted to a pluripotent stem cell is stimulating efforts to force selected cell types of one tissue to be converted directly into the cells of another tissue. The field of hematology has led many of these developments, with several clinical applications currently under development, as will be discussed in this chapter.

A second major discovery of the decade has been the development of new methods for targeted alteration ...

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