Split ends in CML: divergent roles of Hes1

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 

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.