Recurrent Missense Driver STAT5B ^N642H Mutation in Children Transiting into Adolescence, with Acute Lymphoid Leukemia...

The occurrence of gain of function mutations in STAT5B has been associated to survival, and drug resistance in Leukemia. In silico screening of compounds having inhibitory potential towards mutated proteins, can be helpful in the development of specific inhibitors.

This study was designed to screen selected JAK-STAT mutations in leukemia patients and virtual exploration of molecular interaction of potential inhibitors with their mutated products.

In total 276 patients were randomly recruited for this study. Demographic and clinical data were summarized. The genetic status of JAK1^V623A, JAK2 ^S473 and STAT5B^N642H were screened through allele specific PCR. In-silico analysis was performed on wild type and mutant protein sequences retrieved from Protein databank. The ligands and protein were prepared through standard protocols, and docking was performed through Auto Dock Vina 1.2.0.

Acute lymphoblastic leukemia comprises 70% of the total patients. Male to female ratio was 3:1. All the patients were homozygous for JAK1^V623A, JAK2 ^S473 major allele. However, 6 patients (5 male, 1 female) with ALL were STAT5B^N642H+. The molecular docking of the ligands to wild type and STAT5B^N642H+revealed that AC- 4-130, Pimozide, Indirubin and Stafib-2 have higher but differential docking affinities for SH2-domain of both normal and mutated STAT5B. However, AC-4-130 has a higher affinity for wild type and Stafib-2 has stable molecular interaction with STAT5B^N642H+.

The aggressive form of pediatric leukemia, carrying STAT5B^N642H+ mutation is identified in the studied population. It is predicted that AC-14-30 and stafib-2 have potential for inhibition of constitutively active STAT5B if optimized for use in combination therapy.