Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice

Abstract

Acute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis, whose largest subgroup is characterized by somatic mutations in NPM1, the gene for Nucleophosmin1. These mutations, termed NPM1c, result in cytoplasmic dislocation of Nucleophosmin1 and are associated with distinctive transcriptional signatures2, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in murine hemopoietic stem cells causes Hox overexpression, enhanced self-renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty3-4 transposon which caused rapid-onset AML in 80% of Npm1c+ mice, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. Recurrent integrations were also identified in known and novel leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results give new pathogenetic insights and identify therapeutic targets in NPM1c+ AML.

Emerging Roles of the Nucleolus in Regulating the DNA Damage Response: The Noncanonical DNA Repair Enzyme APE1/Ref-1 as a Paradigmatical Example

“…More importantly, emerging evidences further highlight the importance of nucleolar hub proteins in human pathology. The link between NPM1 and oncogenesis, for example, is a well-established paradigm (31,52,151) and we recently demonstrated that in acute myeloid leukemia bearing NPM1 mutations, the cytoplasmic de-localization of the mutant NPM1c + leads to extensive BER impairment due to APE1 nuclear deprivation (150). This evidence denotes how the deregulation of an important nucleolar factor might impact on the overall cellular dynamics and not only on the ribosome biogenesis, supporting the view of the nucleolus as a multifunctional and versatile organelle.…”

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

“…We also determined that the biologic effects of SP2509 treatment were also phenocopied by shRNA mediated knockdown of LSD1 in AML cells, suggesting that the effects of SP2509 were mediated by LSD1 inhibition. Recent reports have highlighted that the NPM1 mutation is the founder mutation in the AML stem/progenitor cells where acquisition of FLT3-ITD mutation results in the emergence of an aggressive AML phenotype (4,34). In our studies, SP2509 exerted a relatively higher level of activity against AML cells expressing NPM1 mutation.…”

Clinical and Biological Relevance of Gene Expression Profiling in Acute Myeloid Leukemia

“…Expression of FLT3 mutants in murine 32Dcl3 cells resulted in repression of genes involved in myeloid differentiation, including CEBPA, and in the activation of a transcriptional program that partially overlaps with that induced by IL-3, a potent hematopoietic cytokine (Mizuki et al 2003). Recently, the expression of an NPM1 mutant allele in mouse HSC was shown to result in HOX gene overexpression, reproducing the situation of primary AML with mutated NPM1 (Vassiliou et al 2011). The molecular mechanisms through which these mutants elicit a transcriptional response remain to be elucidated.…”