Abstract 2940: Altered hematopoiesis and lymphomagenesis through loss of chromatin-associated protein KIF4

Abstract

Abstract Hematopoiesis, the process of blood cell formation is largely dependent on specialized chromatin environment for stem cell self-renewal and multi-lineage differentiation. The kinesin motor protein KIF4 associates with chromatin during interphase, performs essential functions in mitosis and its loss causes hypercondensation of mitotic chromosomes leading to genomic instability. We have demonstrated that KIF4 is a modulator of interphase chromatin architecture. In KIF4-null mouse ES cells, heterochromatin blocks are lost, pericentormeric heterochromatin regions are decondensed in S phase and chromatin is globally decondensed. The global chromatin decondensation has functional consequences as indicated by mis-regulation of significant number of genes detected by microarray expression analysis. To understand the molecular mechanism of KIF4 function in vivo, we have developed KIF4 knockout (KIF4 KO) mouse. Here we show that in the absence of KIF4 animals develop splenomegaly, substantial populations of mice have thymic and splenic hyperplasia and ∼40% of heterozygous female mice developed Follicular B cell lymphoma similar to human Non-Hodgkin lymphoma. Flow sorting (FACS) analysis of young mice indicated that loss of KIF4 causes defects in hematopietic development and differentiation. Lymphocytes from animals lacking KIF4 exhibit chromatin defects, aneuploidy, DNA damage and slow progression of lymphocytes through cell cycle. More importantly, we find that there is an accumulation of mature B cells in the spleen in the absence of KIF4. The increased survival of germinal center B cells in the absence of KIF4 may cause the observed hyperplasia and B cell neoplasm. The mechanism of survival and expansion of lymphocytes in spite of genomic instability could be linked to the defects in chromatin organization and changes in transcriptional potential. We propose KIF4 may act as a modulator of chromatin function to regulate cell fate decision during lymphocyte development and a guardian of genome stability to prevent hematopoietic neoplasm. Hematologic malignancy via deletion of a chromatin-associated molecular motor protein is a novel paradigm both in the fields of molecular motors and cancer biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2940.