Effect of transcription-factor concentrations on leukemic stem cells

Abstract

Increasing evidence suggests that leukemias are sustained by leukemic stem cells. However, the molecular pathways underlying the transformation of normal cells into leukemic stem cells are still poorly understood. The involvement of a small group of key transcription factors into this process was suggested by their frequent mutation or down-regulation in patients with acute myeloid leukemia (AML). Recent findings in mice with hypomorphic transcription-factor genes demonstrated that leukemic stem-cell formation in AML could directly be caused by reduced transcription-factor activity beyond a critical threshold. Most interestingly, those experimental models and the paucity of biallelic null mutations or deletions in transcription-factor genes in patients suggest that AML is generally associated with graded down-regulation rather than complete disruption of transcription factors. Here, we discuss the effects of transcription-factor concentrations on hematopoiesis and leukemia, with a focus on the regulation of transcription-factor gene expression as a major mechanism that alters critical threshold levels during blood development and cancer.

Figure 1.

Important stem-cell functions are shared by HSCs and LSCs. Both normal HSCs and neoplastic LSCs have the ability to self-renew and initially differentiate into less pluripotent daughter cells. However, HSCs produce short-lived progenitors, such as common myeloid progenitors (CMPs) and granulocyte monocyte progenitors (GMPs), which terminally differentiate into mature monocytes and granulocytes. In contrast, LSCs give rise to leukemic blasts, which harbor a block in their terminal differentiation. Recent experiments using murine transplantation models suggest that both HSCs and committed myeloid progenitors can transform into an LSC.-

Figure 2.

Model of LSC development by a malignant transcription-factor threshold illustrated on the PU.1 gene. A range of PU.1 expression between normal (100%) and haploinsufficient (50%) levels supports normal HSC differentiation into myeloid progenitors and subsequent mature granulocytes and macrophages. Graded reduction of PU.1 activity below 20% of normal meets a critical threshold level leading to poor differentiation and subsequent accumulation of an abnormal progenitor pool which is reminiscent of a preleukemic phase. Additional secondary mutations, such as c-myc overexpression because of genomic instability, complete the transformation of those cells into LSCs, which give rise to a bulk of AML blasts (leukemic phase). PU.1 function has been shown to be repressed by a number of different mechanisms in human or murine leukemia, which include down-regulation by oncogenic products as well as mutations in the PU.1 coding sequence (CDS) and deletion of the URE.