Chromosome 5q Deletion Syndrome

A number sign (#) is used with this entry because of evidence that the 5q- syndrome is caused by the somatic deletion of 1 allele of the RPS14 gene (130620).

Description

The 5q- syndrome is a myelodysplastic syndrome characterized by a defect in erythroid differentiation. Patients have severe macrocytic anemia, normal or elevated platelet counts, normal or reduced neutrophil counts, erythroid hypoplasia in the bone marrow, and hypolobated micromegakaryocytes (Ebert et al., 2008).

Clinical Features

Van den Berghe et al. (1974) first described refractory macrocytic anemia associated with deletion of the long arm of chromosome 5, which was known as Belgian disease or 'anemie refractaire de type belge.' It was, of course, found not to be limited to Belgium and the 5q- change was found in other hematologic malignancies (see review of Van den Berghe et al., 1985 and Bunn, 1986).

Tinegate et al. (1983) counted 34 recorded cases to the time of their report; 25 were female. A characteristic bone marrow finding is the presence of numerous unilobular nucleated megakaryocytes; the nucleus is often eccentric with copious granular cytoplasm exhibiting plentiful production of large platelets. The clinical course is relatively mild. Transformation into acute nonlymphocytic leukemia is rare when there is no other chromosome abnormality than 5q-. Desferrioxamine administration was recommended to lessen the complications of hemosiderosis.

Stuart and Mangan (1986) described successful treatment with syngeneic bone marrow transplantation. When first seen at age 29 years, the patient had the picture of pure red cell aplasia and normal marrow karyotype but with hypolobulated megakaryocytic nuclei. The anemia did not respond to any medical therapy. Two years later he showed the 5q- abnormality in 70% and later 100% of marrow metaphases. Because of transfusion-induced hemosiderosis and the availability of a cytogenetically normal monozygotic twin, bone marrow transplantation was performed. The patient's marrow was ablated with a busulfan plus cyclophosphamide regimen used for patients with nonlymphocytic leukemia. Sustained engraftment of cytogenetically normal marrow ensued. The 5q- myelodysplastic syndrome typically occurs in older persons, particularly females. The deletion is usually interstitial; the distal breakpoint is usually in 5q32 and the proximal breakpoint in 5q12-q14.

Mathew et al. (1993) reported the experience with 43 consecutive patients seen at the Mayo Clinic in whom the diagnosis was defined by strict morphologic criteria and the finding of a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a female predominance (7:3). Transfusion-dependence was present in 80% of patients at the time of the diagnosis, and all untransfused patients had macrocytic indices. In contrast, significant neutropenia or thrombocytopenia was rare.

Clinical Management

Nimer (2006) reviewed the clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q. Lenalidomide is particularly active in treating the anemia of del(5q) myelodysplastic syndrome, which is especially relevant given the low response rate to erythropoietin in this group of patients. The author noted that only a subset of patients with del(5q) MDS fulfill the WHO diagnostic criteria for the 5q- syndrome: de novo myelodysplastic syndrome with an isolated 5q interstitial deletion involving 5q31-q33, macrocytic anemia, less than 5% blasts in the peripheral blood, and a normal or increased platelet count.

Lenalidomide is a highly effective treatment for myelodysplastic disease with deletion of chromosome 5q. Kronke et al. (2015) demonstrated that lenalidomide induces the ubiquitination of casein kinase I alpha-1 (CK1-alpha; 600505) by the E3 ubiquitin ligase CUL4 (see 603137)-RBX1 (603814)-DDB1 (600045)-CRBN (609262) (known as CUL4-CRBN), resulting in CK1-alpha degradation. CK1-alpha is encoded by a gene, CSNK1A1, within the common deleted region for del(5q) MDS, and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. Kronke et al. (2015) found that mouse cells are resistant to lenalidomide, but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1-alpha. The authors further demonstrated that minor side-chain modifications in thalidomide and a novel analog, CC-122, can modulate the spectrum of substrates targeted by CRL4-CRBN.

Mapping

By deletion mapping, Boultwood et al. (1994) established the critical region of gene loss in the 5q- syndrome, giving the location for a putative tumor-suppressor gene in the 5.6-Mb region between FGFA (131220) and IL12B (161561). (They referred to the IL12B gene as NKSF1; NKSF2 is the symbol used here for the subunit of interleukin-12 encoded by chromosome 5, and NKSF1, the symbol for the subunit encoded by chromosome 3 (IL12A; 161560).)

Liu et al. (2002) identified 76 zebrafish cDNAs orthologous to genes located in the 2 critically deleted regions on 5q. Radiation hybrid mapping showed that 33 of the 76 zebrafish orthologs are clustered in a genomic region on linkage group 14.

Boultwood et al. (2002) narrowed the common deleted region (CDR) of the 5q- syndrome to the approximately 1.5-Mb interval of chromosome 5q32 flanked by D5S413 and the GLRA1 gene (138491). The CDR contains 24 known and 16 novel (predicted) genes. Of the 40 genes, 33 are expressed in CD34+ cells and therefore represented candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment.

Loss of chromosome 5q is observed in 10 to 15% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; 601626) and in 40% of patients with therapy-related MDS or AML. By cytogenetic analysis and hybridization techniques, Le Beau et al. (1993) identified a common 2.8-Mb critical region on 5q31 that was deleted in 135 patients with hematologic abnormalities and 5q deletions, including 85 patients with de novo MDS or AML, 33 with therapy-related MDS or AML, and 17 with MDS and the 5q deletion syndrome. The EGR1 (128990) gene was included in this critical region. Le Beau et al. (1993) postulated that EGR1 or another closely-linked gene may act as a tumor suppressor gene.

Molecular Genetics

Haploinsufficiency for Ribosomal Protein S14

Somatic chromosomal deletions in cancer are thought to indicate the location of tumor suppressor genes, by which a complete loss of gene function occurs through biallelic inactivation. However, in the 5q- syndrome, no biallelic inactivation had been identified. Ebert et al. (2008) described an RNA-mediated interference-based approach to discovery of the 5q- disease gene. They found that partial loss of function of the ribosomal subunit protein RPS14 (130620) phenocopied the disease in normal hematopoietic progenitor cells, and also that forced expression of RPS14 rescued the disease phenotype in patient-derived bone marrow cells. In addition, the authors identified a block in the processing of preribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anemia (105650), linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure. Ebert et al. (2008) concluded that the 5q- syndrome is caused by defects in ribosomal protein function and suggested that RNA interference screening is an effective strategy for identifying causal haploinsufficiency disease genes.

Haploinsufficiency for MIR145 and MIR146A

Starczynowski et al. (2010) postulated that loss of microRNAs (miRNAs) encoded within the CDR in 5q- syndrome may result in haploinsufficiency due to loss of inhibition of their targets. They found that expression of MIR145 (611795) and MIR146A (610566) was reduced in MDS patients with del(5q). Loss of both MIR145 and MIR146A resulted in activation of innate immune signaling due to elevated expression of their respective targets, TIRAP (606252) and TRAF6 (602355). Knockdown of both Mir145 and Mir146a or overexpression of Traf6 in mouse hematopoietic stem/progenitor cells (HSPCs) recapitulated several features of 5q- syndrome, including thrombocytosis, mild neutropenia, and megakaryocytic dysplasia. Starczynowski et al. (2010) concluded that inappropriate activation of innate immune signals in HSPCs due to loss of miRNA-mediated inhibition is involved in several features of 5q- syndrome.

Haploinsufficiency for DDX41

Polprasert et al. (2015) presented evidence that haploinsufficiency for the DDX41 gene (608170) may contribute to the 5q- syndrome in some cases (see MPLPF, 616871).

Pathogenesis

Using 579 probe sets to examine gene expression of proteins involved in ribosomes and translation, Pellagatti et al. (2008) found that bone marrow-derived CD34+ cells of 15 patients with 5q- syndrome and MDS had significant differential expression in 55 genes, of which 49 (89%) genes showed significantly decreased expression, compared to 18 MDS patients with refractory anemia and normal karyotype and 17 healthy controls. A 2-way scatterplot using 2 of the most significant genes identified could effectively separate the patients with 5q- syndrome from the patients with refractory anemia and controls. RT-PCR analysis confirmed downregulation of RPL28 (603638), RPS14, and EEF1D (130592) and upregulation of TNFRSF10B (603612) and BAX (600040) in the 5q- syndrome. Changes in gene expression were similar to those found by Gazda et al. (2006) in Diamond-Blackfan anemia. Pellagatti et al. (2008) concluded that the 5q- syndrome results from dysregulation of ribosomal gene expression, ribosomal biogenesis, and impaired protein synthesis and translation.

Animal Model

Joslin et al. (2007) reported that Egr1 -/- and Egr1 +/- mice treated with N-ethyl-nitrosourea developed a myeloproliferative disorder with some features of human myeloid disorders associated with 5q deletion. The phenotype was characterized by increased white blood cell counts, anemia, and thrombocytopenia, with ineffective erythropoiesis in bone marrow and spleen. The findings suggested that loss of a single Egr1 allele is sufficient for disease progression in cooperation with secondary mutations.

Varney et al. (2015) observed progressive bone marrow and blood defects, including skewed HSPC proportions and altered myeloid differentiation, in mice lacking Tifab. A subset of mice transplanted with Tifab -/- HSPCs developed bone marrow failure with neutrophil dysplasia and cytopenia. Simultaneous transplantation of Tifab -/- and wildtype HSPCs prevented development of bone marrow failure. Tifab -/- HSPCs were hypersensitive to Tlr4 (603030) stimulation, and loss of Tifab increased Traf6 protein stability and the dynamic range of Tlr4 signaling, contributing to ineffective hematopoiesis. Combined deletion of Tifab and Mir146a, both of which are located within the minimally deleted region in del(5q) MDS/AML, resulted in a cooperative increase in Traf6 expression and hematopoietic dysfunction. Expression of TIFAB in human del(5q) MDS/AML cells with low endogenous TIFAB expression resulted in attenuated TLR4 signaling and reduced viability. Varney et al. (2015) concluded that efficient regulation of innate immune and TRAF6 signaling within HSPCs by TIFAB, and its cooperation with MIR146A, are important in the pathogenesis of del(5q) MDS/AML.

History

The IRF1 gene (147575) on chromosome 5q31 as well as neighboring genes IL5 (147850), CDC25C (157680), IL3 (147740), CSF2 (138960), POP2 (CNOT8; 603731), CSF1R (164770) have been reported as being deleted in 5q- syndrome and are discussed in their respective entries.