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Abstract
Angiogenesis has an important role in pathophysiology of cancer. FMS-like tyrosine kinase 3 (FLT3) is implicated in hematopoietic malignancies. Their role in childhood acute lymphoblastic leukemia (ALL) pathogenesis needs more enlightenment. Expression of vascular endothelial growth factor receptor-1 and -2 (VEGFR-1 and -2), as well as FLT3 were assessed by flow cytometry in bone marrow (BM) blasts of 55 newly diagnosed children with ALL. Patients included B cell ALL (B-ALL) group (n = 41) and T cell ALL (T-ALL) group (n = 14). Comparison between groups revealed a significant increase in blasts percent (%) expressing FLT3 and FLT3 intensity detected in B-ALL group (p = 0.004 and p = 0.02, respectively). In B-ALL patients, a significant positive correlation was seen between blasts % expressing FLT3 and blasts percentage infiltrating BM (r = 0.405; p = 0.009), also positive correlation was seen between % of blasts expressing VEGFR-1 and VEGFR-2 (r = 0.704; p < 0.001). In T-ALL group, blast % expressing FLT3 revealed significant positive correlations with blast % expressing VEGFR-1, and those expressing VEGFR-2 (r = 0.627; p = 0.016, and r = 0.654; p = 0.011, respectively). In addition, significant correlation was seen in blasts % expressing all; FLT3, VEGFR-1 and -2, with blasts % expressing stem cell marker CD34 (r = 0.826; p = 0.001, r = 0.596; p = 0.041, and r = 0.798; p = 0.002, respectively). Conclusion: Expression of VEGFR-1, VEGFR-2 and FLT3 were demonstrated and linked on leukemic blasts of ALL which highlights their role in pathogenesis. FLT3 expression plays a role in facilitating blasts proliferation in BM in B-ALL. FLT3, VEGFR-1 and -2 could be used in future profiling of CD34+ leukemic stem cell pool in T-ALL.
Highlights
Childhood acute lymphoblastic leukemia (ALL) comprises about 30% of malignancies in childhood [1], and constitutes 80% of childhood leukemias [2]
Comparison between groups revealed a significant increase in blasts percent (%) expressing FMS-like tyrosine kinase 3 (FLT3) and FLT3 intensity detected in B cell ALL (B-ALL) group (p = 0.004 and p = 0.02, respectively)
In B-ALL patients, a significant positive correlation was seen between blasts % expressing FLT3 and blasts percentage infiltrating bone marrow (BM) (r = 0.405; p = 0.009), positive correlation was seen between % of blasts expressing vascular endothelial growth factor receptors (VEGFRs)-1 and VEGFR-2 (r = 0.704; p < 0.001)
Summary
Childhood acute lymphoblastic leukemia (ALL) comprises about 30% of malignancies in childhood [1], and constitutes 80% of childhood leukemias [2]. In Egypt, the annual incidence of childhood ALL is about 4 cases per 100,000 children and accounts for approximately 20% of pediatric malignancies [3]. The perturbation in expression of mediators and signaling pathways of angiogenesis have been described in the pathogenesis of hematological malignancies including acute and chronic leukemias, and multiple myeloma [4] [5]. The vascular endothelial growth factor (VEGF) family comprised of ligands and receptors those are key regulators of angiogenesis processes. The vascular endothelial growth factor receptors (VEGFRs), are members of the receptor tyrosine kinase (RTKs) and include three types; VEGFR-1-3. Seven VEGF ligand variants have been identified; VEGF-A-E and placental growth factor (PIGF) [6]. The VEGFR-1 (Flt-1) is located at chromosome 13q12 and VEGFR-2 (KDR/Flk-1) is located at chromosome 4q11 and both are expressed on vascular endothelial cells, whereas VEGFR-3 is expressed on lymphatic endothelial cells [7] [8]
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