STAT5 Gain-of-Function Variants Promote Precursor T-Cell Receptor Activation to Drive T-Cell Acute Lymphoblastic Leukemia

Author:

Suske Tobias,Sorger Helena,Ruge Frank,Prutsch Nicole,Zimmerman Mark W.,Eder ThomasORCID,Maurer Barbara,Wagner Christina,Schönefeldt Susann,Spirk Katrin,Pichler Alexander,Pemovska Tea,Schweicker Carmen,Pölöske Daniel,Jungherz Dennis,Müller Tony Andreas,Aung Myint Myat Khine,Pham Ha Thi Thanh,Zimmel Kerstin,Krausgruber Thomas,Bock ChristophORCID,Müller Mathias,Dahlhoff Maik,Boersma Auke,Rülicke Thomas,Fleck Roman,Gunning Patrick Thomas,Aittokallio Tero,Mustjoki Satu,Sanda Takaomi,Hartmann Sylvia,Grebien Florian,Hoermann Gregor,Haferlach Torsten,Staber Philipp Bernhard,Neubauer Heidi Anne,Look Alfred Thomas,Herling Marco,Moriggl Richard

Abstract

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T-cell cancer. Hotspot mutations in JAK-STAT pathway membersIL7R,JAK1andJAK3were analyzed in depth. However, the role ofSTAT5AorSTAT5Bmutations promoting their hyperactivation is poorly understood in the context of T-cell cancer initiation and acute leukemia progression. Importantly, the driver mutationSTAT5BN642Hencodes the most frequent activating STAT5 variant in T-ALL associated with poor prognosis. Here, we show that hyperactive STAT5 promotes early T-cell progenitor (ETP)-ALL-like cancer in mice and upregulated genes involved in T-cell receptor signaling (TCR), even in absence of surface TCR promoting. Importantly, these genes were also overexpressed in human T-ALL and other STAT5-dependent T-cell cancers. Moreover, human T-ALL cells were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers. Thus, we define STAT5 target genes in T-ALL that promote pre-TCR signaling mimicry. We propose therapeutic targeting using selective ZAP70 or STAT3/5 inhibitors in a subgroup of T-ALL patients with prominent IL-7R-JAK1/3-STAT5 activity.SignificanceWe provide detailed functional characterizations of hyperactive STAT5A or STAT5B in thymic T-cell development and transformation. We found that hyperactive STAT5 transcribes T-cell-specific kinases or pre-TCR signaling hubs to promote T-ALL. Biomolecular and next-generation-sequencing methods, transgenesis and pharmacologic interference revealed that hyperactive STAT5 is a key oncogenic driver that can be targeted in T-ALL using STAT3/5 or SYK family member tyrosine kinase inhibitors.Conflict of interestThe authors declare no potential conflicts of interest.

Publisher

Cold Spring Harbor Laboratory

Reference71 articles.

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