B-cell identity as a metabolic barrier against malignant transformation

Exp Hematol. 2017 Sep:53:1-6. doi: 10.1016/j.exphem.2017.06.004. Epub 2017 Jun 24.

Abstract

B-lineage and myeloid leukemia cells are often transformed by the same oncogenes, but have different biological and clinical characteristics. Although B-lineage acute lymphoblastic leukemia (B-ALL) cells are characterized by a state of chronic energy deficit, myeloid leukemia cells show abundant energy reserve. Interestingly, fasting has been demonstrated to inhibit selectively the development of B-ALL but not myeloid leukemia, further suggesting that lineage identity may be linked to divergent metabolic states in hematopoietic malignancies. The B-lymphoid transcription factors IKZF1, EBF1, and PAX5 are essential for early B-cell development and commitment to B-cell identity. However, in >80% of human pre-B-ALL cases, the leukemic clones harbor genetic lesions of these transcription factors. The significance of these defects has only recently been investigated. Here, we discuss the unexpected function of a B-lymphoid transcriptional program as a metabolic barrier against malignant transformation of B-cell precursor cells. The metabolic gatekeeper function of B-lymphoid transcription factors may force silent preleukemic clones carrying potentially oncogenic lesions to remain in a latent state. In addition, this program sets the threshold for responses to glucocorticoids in pre-B-ALL. Finally, the link between the tumor-suppressor and metabolic functions of B-lymphoid transcription factors is matched by observations in clinical trials: obesity and hyperglycemia are associated with poor clinical outcome in patients with pre-B-ALL.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • Cell Lineage
  • Cell Transformation, Neoplastic*
  • Energy Metabolism
  • Forkhead Box Protein O1 / physiology
  • Humans
  • Ikaros Transcription Factor / physiology
  • Mice
  • Obesity / complications
  • PAX5 Transcription Factor / physiology
  • Phosphatidylinositol 3-Kinases / physiology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / etiology*
  • Proto-Oncogene Proteins c-akt / physiology
  • Receptors, Leptin / physiology

Substances

  • Forkhead Box Protein O1
  • IKZF1 protein, human
  • PAX5 Transcription Factor
  • Receptors, Leptin
  • Ikaros Transcription Factor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt