Loss of Histone Locus Bodies in the Mature Hemocytes of Larval Lymph Gland Result in Hyperplasia of the Tissue in mxc Mutants of Drosophila.

Masanori Kurihara,Kouyou Komatsu,Rie Awane,Yoshihiro H Inoue

doi:10.3390/ijms21051586

Masanori Kurihara, Kouyou Komatsu + Show 2 more

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https://doi.org/10.3390/ijms21051586

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Abstract

Mutations in the multi sex combs (mxc) gene in Drosophila results in malignant hyperplasia in larval hematopoietic tissues, called lymph glands (LG). mxc encodes a component of the histone locus body (HLB) that is essential for cell cycle-dependent transcription and processing of histone mRNAs. The mammalian nuclear protein ataxia-telangiectasia (NPAT) gene, encoded by the responsible gene for ataxia telangiectasia, is a functional Mxc orthologue. However, their roles in tumorigenesis are unclear. Genetic analyses of the mxc mutants and larvae having LG-specific depletion revealed that a reduced activity of the gene resulted in the hyperplasia, which is caused by hyper-proliferation of immature LG cells. The depletion of mxc in mature hemocytes of the LG resulted in the hyperplasia. Furthermore, the inhibition of HLB formation was required for LG hyperplasia. In the mutant larvae, the total mRNA levels of the five canonical histones decreased, and abnormal forms of polyadenylated histone mRNAs, detected rarely in normal larvae, were generated. The ectopic expression of the polyadenylated mRNAs was sufficient for the reproduction of the hyperplasia. The loss of HLB function, especially 3′-end processing of histone mRNAs, is critical for malignant LG hyperplasia in this leukemia model in Drosophila. We propose that mxc is involved in the activation to induce adenosine deaminase-related growth factor A (Adgf-A), which suppresses immature cell proliferation in LG.

Highlights

Leukemia encompasses a group of blood cancers that usually develop in the bone marrow and result in the production of excessive abnormal blood cells [1,2,3]
We further investigated whether the development of lymph glands (LG) hyperplasia in the LGs was affected in the hemizygotes for lethal alleles
pericardial cells (PC) cells are originally localized between lobes in normal LGs (Supplementary Figure S1a’), they are positioned at the anterior end of the most enlarged lobe in both hemispheres of the mutant LG

Summary

Introduction

Leukemia encompasses a group of blood cancers that usually develop in the bone marrow and result in the production of excessive abnormal blood cells [1,2,3]. Mutations in many genes that are responsible for the pathogenesis of leukemia have been identified via genome analysis of patient-derived leukemic cells [4,5,6]. Recent studies have attempted to identify and characterize new genes that are involved in leukemia and related diseases. Previous studies have indicated that mutations in NPAT are related to a class of malignant lymphomas, called Hodgkin’s lymphoma [7,8]. This gene is involved in ataxia disorder, which is associated with cancer-related symptoms [9]. NPAT/p220 is a transcription factor that controls cell cycle-dependent histone gene transcription in an E2F-dependent manner [12]. The mechanisms underlying the alteration of expression and/or function of the proteins that eventually led to tumorigenesis of hematopoietic cells are still not known

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