A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene

Blood. 2009 Jan 29;113(5):1075-85. doi: 10.1182/blood-2008-03-144436. Epub 2008 Oct 23.

Abstract

NF1 inactivation occurs in specific human cancers, including juvenile myelomonocytic leukemia, an aggressive myeloproliferative disorder of childhood. However, evidence suggests that Nf1 loss alone does not cause leukemia. We therefore hypothesized that inactivation of the Nf1 tumor suppressor gene requires cooperating mutations to cause acute leukemia. To search for candidate genes that cooperate with Nf1 deficiency in leukemogenesis, we performed a forward genetic screen using retroviral insertion mutagenesis in Nf1 mutant mice. We identified 43 common proviral insertion sites that contain candidate genes involved in leukemogenesis. One of these genes, Bcl11a, confers a growth advantage in cultured Nf1 mutant hematopoietic cells and causes early onset of leukemia of either myeloid or lymphoid lineage in mice when expressed in Nf1-deficient bone marrow. Bcl11a-expressing cells display compromised p21(Cip1) induction, suggesting that Bcl11a's oncogenic effects are mediated, in part, through suppression of p21(Cip1). Importantly, Bcl11a is expressed in human chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia samples. A subset of AML patients, who had poor outcomes, of 16 clusters, displayed high levels of BCL11A in leukemic cells. These findings suggest that deregulated Bcl11a cooperates with Nf1 in leukemogenesis, and a therapeutic strategy targeting the BCL11A pathway may prove beneficial in the treatment of leukemia.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Transformed
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA-Binding Proteins
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelomonocytic, Juvenile / genetics
  • Leukemia, Myelomonocytic, Juvenile / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutagenesis, Insertional / methods
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Repressor Proteins
  • Retroviridae

Substances

  • BCL11A protein, human
  • Bcl11a protein, mouse
  • CDKN1A protein, human
  • Carrier Proteins
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • Neurofibromin 1
  • Nuclear Proteins
  • Repressor Proteins