A chromosomal deletion is a genetic alteration involving the loss of a segment of a chromosome. The missing segment can range in size from a single DNA base pair up to an entire arm of the chromosome. The term “5q deletion” specifically refers to the loss of genetic material from the long arm (q arm) of chromosome 5. This alteration is an acquired change that occurs in blood-forming cells; it is not inherited but develops during a person’s lifetime. The deletion is represented in cytogenetic notation as del(5q), and its presence is directly associated with the development of certain blood disorders.
Biological Consequences of the Deletion
The biological problems resulting from the 5q deletion stem from the loss of one copy of numerous genes in the affected region, a mechanism known as haploinsufficiency. Since the remaining single copy of these genes cannot produce enough protein for normal cell function, the process of blood cell production, or hematopoiesis, becomes disrupted. The most commonly deleted area, known as the Common Deleted Region (CDR), contains approximately 40 genes located between bands 5q31 and 5q33.
One gene in this region, RPS14, encodes a ribosomal protein involved in building the cell’s protein-making machinery. Haploinsufficiency of RPS14 triggers a cellular stress response, leading to the activation of the tumor suppressor protein p53. This activation causes the premature death of red blood cell precursors in the bone marrow, which directly results in the characteristic severe anemia seen in patients.
The loss of two microRNA molecules, miR-145 and miR-146a, also contributes to the disease’s unique features. Their absence leads to the abnormal development of megakaryocytes, the cells responsible for platelet formation. Additionally, the deletion includes the CSNK1A1 gene, a protein kinase that, when reduced by haploinsufficiency, makes the abnormal cells uniquely vulnerable to targeted drug treatment. The cumulative impact of losing these multiple genes leads to ineffective and abnormal production of all blood cell lines.
Clinical Presentation in Myelodysplastic Syndrome
The 5q deletion is most commonly linked to a specific, lower-risk subtype of Myelodysplastic Syndrome (MDS), a group of cancers characterized by ineffective blood cell formation. This specific subtype is formally classified as MDS with isolated del(5q) when the deletion is the sole or primary chromosomal abnormality. Patients typically present with symptoms related to a shortage of red blood cells, such as debilitating fatigue, paleness, and shortness of breath.
The anemia found in this syndrome is characteristically macrocytic, meaning the red blood cells that are present are abnormally large. A distinctive feature of this particular MDS subtype is the pattern of platelet counts, which are often normal or even elevated, a condition called thrombocytosis. This is unusual for most forms of MDS, which typically involve low platelet counts.
Examination of the bone marrow reveals a highly characteristic cellular pathology. The marrow is often normocellular or hypercellular, meaning it contains a normal or higher-than-normal number of cells, but most of these cells are abnormal and dysfunctional. A key finding is an increased number of megakaryocytes, which are the precursor cells for platelets.
These megakaryocytes display a highly atypical morphology, appearing small with non-lobulated or hypolobulated nuclei, often described as monolobulated. The definition of this MDS subtype requires that the percentage of immature blood cells, or blasts, in the bone marrow be low, specifically less than five percent. This low blast count and the isolated nature of the deletion classify it as a relatively favorable prognosis compared to other MDS subtypes.
Diagnostic Identification of the Abnormality
The identification of the 5q deletion begins with an analysis of a bone marrow sample, which is necessary because the abnormality resides in the hematopoietic cells. Conventional cytogenetics, or karyotyping, is the standard method for visualizing chromosomes and is used to detect the deletion. This technique involves culturing and staining the cells to allow scientists to physically arrange and examine all 46 human chromosomes under a microscope.
The deletion is recognized by the missing segment on one of the two copies of chromosome 5 and is recorded using the standardized notation del(5q). Fluorescence In Situ Hybridization (FISH) serves as an important complementary technique, especially for detecting small deletions that may be missed by karyotyping. FISH uses fluorescently labeled DNA probes that bind only to the specific region of the chromosome in question, such as the 5q31 locus.
This molecular technique can detect the loss even in non-dividing cells (interphase nuclei), providing a more sensitive method for finding the deletion or confirming it when a karyotype is inconclusive. The combined use of both karyotyping and FISH ensures a comprehensive and accurate diagnosis of the 5q deletion.
Targeted Treatment Strategies
The identification of the 5q deletion points to a highly effective, targeted treatment strategy. The primary therapy for patients with MDS associated with del(5q) who require red blood cell transfusions is the immunomodulatory drug Lenalidomide. Lenalidomide works by selectively inducing cell death in the abnormal cells carrying the 5q deletion.
The drug exploits the vulnerability created by the haploinsufficiency of the CSNK1A1 gene, which is located within the deleted region. Lenalidomide binds to a protein called cereblon, which then tags the remaining CK1α protein for degradation, preferentially eliminating the del(5q) clone. This targeted action leads to robust responses, with a high percentage of patients achieving transfusion independence and clearance of the abnormal clone from the bone marrow.
Supportive care like red blood cell transfusions remains a necessary component of management for many patients, especially before the drug takes effect. For patients whose disease progresses or who fail to respond to Lenalidomide, alternative treatments are necessary. These alternatives can include other hypomethylating agents or, in younger and fitter patients, an allogeneic stem cell transplant, which is the only potentially curative option.