Hairy enhancer of split 1 (Hes1), a basic helix-loop-helix transcription factor mediator of Notch signaling, maintains hematopoietic and neuronal stem cell self-renewal as well as fetal T-cell and malignant CML progenitor immaturity, according to Nakahara and colleagues in this issue of Blood.1-6 

While Notch1-activating mutations are detectable in more than half of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases,5  the role of Notch signaling in chronic myeloid leukemia (CML) transformation has not been completely elucidated. An emerging theme in the malignant progression of a number of leukemia subtypes is acquisition of unbridled self-renewal potential by committed progenitors. In CML, both Wnt/β-catenin and sonic hedgehog (Shh) pathway activation have been shown to promote blast crisis transformation and progenitor self-renewal.7,8 

While retrovirally enforced expression of BCR-ABL in hematopoietic stem (Kit+Sca+Lin [KSL]) cells initiates and drives development of chronic-phase CML, the transition to blast crisis is promoted by Hes1-mediated prevention of common myeloid (CMP) or granulocyte macrophage (GMP) progenitor (purple) differentiation.

While retrovirally enforced expression of BCR-ABL in hematopoietic stem (Kit+Sca+Lin [KSL]) cells initiates and drives development of chronic-phase CML, the transition to blast crisis is promoted by Hes1-mediated prevention of common myeloid (CMP) or granulocyte macrophage (GMP) progenitor (purple) differentiation.

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In their compelling article, Nakahara and colleagues demonstrate that retrovirally enforced expression of BCR-ABL in c-Kit+Sca+Lin (KSLs) cells transplanted into irradiated mice leads to manifestations of chronic-phase CML, whereas BCR-ABL expression in common myeloid progenitors (CMPs) or granulocyte-macrophage progenitors (GMPs) does not. Conversely, combined retroviral expression of BCR-ABL and Hes1 in CMPs or GMPs results in blast-crisis transformation. In the absence of BCR-ABL, expression of Hes1 in myeloid progenitors does not support development of leukemia in recipient irradiated mice, demonstrating the need for synergistic interactions between Hes1 and BCR-ABL. Leukemic cells derived from progenitors expressing both Hes1 and BCR-ABL were more immature than those derived from KSLs expressing BCR-ABL alone. Moreover, enforced expression of a dominant- negative form of Hes1 inhibited the growth of Hes1-expressing CML cell lines. Finally, detection of elevated Hes1 expression in 8 of 20 blast crisis samples compared with low-level expression in chronic-phase samples supports a role for Hes1 in some cases of blast crisis CML.1 

During normal development, Notch, Wnt, and Shh pathways work in concert to regulate embryonic patterning, cell polarity, determination of cell fate, and self-renewal. Although Hes1 is a well-defined transcriptional mediator of Notch signaling, recent studies in neuronal precursor cells suggest that the Notch1 intracellular domain (NICD) and β-catenin form a molecular complex that promotes Hes1 expression and neural stem cell maintenance.8,9  Conceivably, a similar mechanism could prevent differentiation and promote maintenance of malignant CML progenitors through self-renewing divisions. Notably, in other reports Hes1 expression has been shown to be up-regulated in a canonical Notch signaling–independent manner through an essential mediator of sonic hedgehog signaling, smoothened.10  Moreover, enhanced Hes1 expression leads to expansion of myeloid progenitors1  and prevents granulocyte differentiation by blocking C-enhancer binding protein-α. Hence, enhanced Hes1 expression may promote both myeloid immaturity and blast crisis transformation through a number of different mechanisms.

This study by Nakahara and colleagues has important implications for diagnosis, prognosis, and treatment of CML. A number of effective BCR-ABL inhibitors currently in clinical use maintain cytogenetic remissions in chronic-phase CML. However, a growing proportion of patients are showing evidence of disease progression as a result of resistance or intolerance to sustained BCR-ABL inhibitory regimens. Early detection of enhanced Hes1 expression in BCR-ABL inhibitor–resistant patients may provide a vital opportunity to expunge a root cause of blast crisis transformation through combined BCR-ABL and Hes1 inhibitor treatment. Combined molecularly targeted therapy may obviate the divergent path taken by myeloid progenitors that promote transition to blast crisis.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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