Twins with different personalities: STAT5B—but not STAT5A—has a key role in BCR/ABL-induced leukemia

Abstract

Deregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is found in cancer with STAT5A/B controlling leukemic cell survival and disease progression. As mutations in STAT5B, but not STAT5A, have been frequently described in hematopoietic tumors, we used BCR/ABL as model systems to investigate the contribution of STAT5A or STAT5B for leukemogenesis. The absence of STAT5A decreased cell survival and colony formation. Even more drastic effects were observed in the absence of STAT5B. STAT5B-deficient cells formed BCR/ABL+ colonies or stable cell lines at low frequency. The rarely evolving Stat5b−/− cell lines expressed enhanced levels of BCR/ABL oncoprotein compared to wild-type cells. In line, Stat5b−/− leukemic cells induced leukemia with a significantly prolonged disease onset, whereas Stat5a−/− cells rapidly caused a fatal disease superimposable to wild-type cells. RNA-sequencing (RNA-seq) profiling revealed a marked enhancement of interferon (IFN)-α and IFN-γ signatures in Stat5b−/− cells. Inhibition of IFN responses rescued BCR/ABL+ colony formation of Stat5b−/−-deficient cells. A downregulated IFN response was also observed in patients suffering from leukemia carrying STAT5B mutations. Our data define STAT5B as major STAT5 isoform driving BCR/ABL+ leukemia. STAT5B enables transformation by suppressing IFN-α/γ, thereby facilitating leukemogenesis. Our findings might help explain the high frequency of STAT5B mutations in hematopoietic tumors.

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

“…This matches the described STAT5-IFN axis in transformation. 45 Stat5a and Stat5b share very similar roles in T-cells. 46 However, sequencing efforts attribute an important role to the activating STAT5B N642H variant.…”

Involvement of STAT5 in Oncogenesis

“…Unlike in solid tumours, mutations in STAT5 are more common in driving its constitutive activation in the various haematological cancers [ 97 ]. Kollman et al discovered that somatic mutations in STAT5b, such as the SH2 domain mutation of STAT5b N642H, inhibited interferon-α/γ (IFNα/γ) signalling in Bcr-Abl-driven leukaemia, thus promoting tumour formation and growth [ 81 , 98 ]. These mutations occur more frequently in STAT5b than in STAT5a, and STAT5b was also elucidated to play a more prominent role in the initiation and progression of these malignancies than STAT5a [ 81 ].…”

STAT5A and STAT5B—Twins with Different Personalities in Hematopoiesis and Leukemia

“…It impairs TPO signaling, which finally ends up in lower HSC self-renewal and reconstitution [125,126,127]. Vice versa, activated STAT5B may repress IFN-α/β and IFN-γ signaling in HSCs, as has been recently demonstrated in transformed pro-B cells [128].…”

“…The relevance of this finding is supported by data from human patients suffering from STAT5B -GOF mutant PTCL. There, the picture was inverse: IFN signaling was downregulated upon STAT5B hyperactivation [128].…”