STAT5A mutation

In conclusion, our study provides valuable insights into the prevalence and characteristics of JAK2, CALR, and MPL mutations in BCR-ABL1 negative MPNs in the Moroccan population, highlighting the importance of genetic characterization to optimize the clinical management of these diseases.

The JAK1/2 inhibitor, ruxolitinib, which increased the uSTAT5:pSTAT5 ratio, had similar effects on murine HSC function: it constrained HSC differentiation and proliferation, promoted HSC maintenance and upregulated transcriptional programs associated with stemness...Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function and highlight JAK inhibition as a potential strategy for enhancing HSC function during ex vivo culture. Increased levels of uSTAT5 may also contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.

The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.

While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

In the mechanistic study, these pernicious phenotypes driven by noncanonical mutations might be initial PMF by activating p-STAT5a/c-Myc/CyclinD1 and p-STAT3/p-AKT/p-ERK1/2 signaling axes. Therefore, our study explored the deleterious roles of novel noncanonical mutations in STAT5a and SH2B3, which may serve as susceptibility genes and display the oncogenic biofunction in the progression of PMF to acute myeloid leukemia-M2a (AML-M2a).

Here we describe the important steps required to generate retroviral particles for the stable expression of mutant JAK3 constructs that induce constitutive JAK/STAT signaling. These are subsequently used for the viral transduction of the IL-3 cytokine-dependent Ba/F3 cell line or murine hematopoietic stem and progenitor cells (HSPCs) for in vitro and in vivo modelling of cytokine-independent growth or leukemia initiation respectively.

Our study demonstrated that our MPN patients have a similar genetic landscape to other MPN populations, with >93% being able to be diagnosed by testing for the JAK2V617F and CALR exon9 mutations alone. Adoption of the WHO 2016 guidelines is recommended to guide testing practices.