What is the genetic basis of elevated White Blood Cell (WBC) count?

From the Guidelines

Genetic elevation of white blood cell count is a condition where individuals have persistently high white blood cell counts due to genetic factors, and it is essential to distinguish this condition from reactive leukocytosis or malignant causes like leukemia, with management focusing on reducing the risk of complications such as leukostasis and tumor lysis syndrome, as recommended by the 2024 ELN guidelines 1. The condition can be caused by various genetic mutations that affect the production, maturation, or lifespan of white blood cells. Some specific genetic disorders associated with elevated white blood cell counts include hereditary neutrophilia, familial cold autoinflammatory syndrome, and certain leukocyte adhesion deficiency syndromes.

• These genetic conditions typically result in white blood cell counts that are consistently above the normal range (typically 4,500-11,000 cells per microliter in adults), even in the absence of infection or inflammation.
• The elevation is usually detected during routine blood tests and remains stable over time.
• While most cases of hereditary leukocytosis are benign and don't require treatment, it's crucial to monitor and manage the condition to prevent complications, as recommended by the European LeukemiaNet guidelines 1.
• In cases where family history suggests an inherited pattern of elevated white blood cell counts, genetic testing can help confirm the diagnosis, as noted in the NCCN guidelines 1.
• Management of symptomatic leukostasis, which can occur in patients with very high WBC, involves reducing the WBC count to prevent tissue damage and organ compromise, with options including hydroxyurea, leukapheresis, and supportive care, as recommended by the European LeukemiaNet guidelines 1.

From the Research

Genetic Elevation of White Blood Count

• The genetic elevation of white blood count is often associated with myeloproliferative neoplasms, such as chronic myeloid leukemia (CML) 2, 3, 4, 5.
• CML is characterized by the presence of the Philadelphia chromosome, which is defined by the BCR::ABL1 oncogene that develops after fusion of the ABL1 proto-oncogene to the constitutively active BCR gene 2, 5.
• The BCR-ABL1 fusion oncogene leads to an increased production of white blood cells, resulting in an elevated white blood cell count 2, 5.
• Other genetic alterations, such as CALR mutations, have also been identified in patients with myeloproliferative neoplasms 4.
• The evaluation of patients with leukocytosis (elevated white blood cell count) requires a comprehensive approach, including repeat complete blood count with peripheral smear, leukocyte differential, and consideration of potential etiologies such as infection, medication, or hematologic malignancy 6.

Tyrosine Kinase Inhibitors and White Blood Cell Count

• Tyrosine kinase inhibitors (TKIs) are a class of medications used to treat CML and other myeloproliferative neoplasms 2, 3, 5.
• TKIs, such as imatinib, nilotinib, dasatinib, and bosutinib, have been shown to improve survival rates in patients with CML by reducing the white blood cell count and inducing a complete molecular response 2, 5.
• However, some patients may develop resistance to TKIs, including the T315I "gatekeeper" mutation, which can lead to an increased white blood cell count and disease progression 5.

Clinical Implications

• The management of patients with an elevated white blood cell count requires a multidisciplinary approach, including hematologists, oncologists, and other healthcare professionals 2, 6, 5.
• Patients with CML or other myeloproliferative neoplasms should be closely monitored for signs and symptoms of disease progression, including an increased white blood cell count, and should receive prompt treatment with TKIs or other therapies as indicated 2, 5.