STAT5B N642H

The simulation predictions of the effects of the mutation on structure and dynamics are supported by the results of hydrogen-deuterium exchange (HDX) mass spectrometry measurements carried out on STAT5B and STAT5BN642H in which a phosphopeptide was used to mimic the effects of parallel dimerization on the SH2 domain. The molecular-level information uncovered in this work contributes to our understanding of STAT5B hyperactivation by the N642H mutation and could help pave the way for novel therapeutic strategies targeting this mutation.

We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.

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.

We have generated the first reliable STAT5BN642H-driven pre-clinical mouse model that displays an indolent NK-LGLL progressing to aggressive NK-cell leukemia. This novel in vivo tool will enable us to explore the transition from an indolent to an aggressive disease and will thus permit the study of prevention and treatment options for NK-cell malignancies.

We previously demonstrated that PD-L1 is significantly up-regulated in AML patients who carry mutant JAK2/STAT when compared to WT JAK2. Using a proposed PD-L1 CPS cut-off score of 20, we demonstrated that high PD-L1 expression was associated with significantly worse outcomes with respect to OS and EFS. These results may indicate a therapeutic role of immunotherapy in the treatment of AML, particularly in patients with JAK2/STAT mutations.

T-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.

In the AML patients with oncogenic JAK2 or its downstream signaling molecule STAT5B mutations, there is significantly enhanced PD-L1 expression. In addition, we proposed that the PD-L1 CPS positivity cut-off score of 10 being used as a quantitative measure of PD-L1 expression in this heterogeneous myeloid neoplasm. In the patient with relapsing AML, PD-L1 expression showed a positive correlation with increased JAK2 mutant VAF.

Exploring the underlying mechanisms will contribute to a better understanding of the complex regulation of NK-cell activity. This might have implications for immunotherapeutic approaches using cytokines that activate STAT5 to expand and stimulate NK cells.

New therapeutic strategies are needed to overcome the overall survival of two years observed in T-PLL patients even after treatment with alemtuzumab and consolidation with allogeneic stem cell transplantation. This hypothesis is further sustained by the same response to the treatment with Bz. Since the treatment of T-PLL mostly remains an unmet clinical need, the finding of an increased apoptosis in Bz-treated cells paves the way for a deeper study on molecular mechanisms involved in the apoptosis of the leukemic clone.

Additionally, we further confirmed the previously reported clonal dominance of TRBV6-expressing clones in CD4+ T-LGLL. In conclusion, CD4+ T-LGLL patients have a typical TCR and mutation profile suggestive of aberrant antigen response underlying the disease.