STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27 and upregulation of the transferrin receptor, CD71. Surprisingly, STAT5 inhibition does not significantly affect IL-7-mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism. STAT5 chromatin immunoprecipitation sequencing and RNA sequencing reveal a diverse IL-7-driven STAT5-dependent transcriptional program in T-ALL cells, which includes inactivation by alternative transcription and upregulation of the oncogenic serine/threonine kinase Pharmacological inhibition of PIM1 abrogates IL-7-mediated proliferation on T-ALL cells, indicating that strategies involving the use of PIM kinase small-molecule inhibitors may have therapeutic potential against a majority of leukemias that rely on IL-7 receptor (IL-7R) signaling. Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R.

Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes

“…Furthermore, we demonstrate the synergistic potential of combining DEX with these agents and propose that combination therapy may allow for a reduction in DEX dosing, thereby minimizing the numerous acute and chronic toxicities associated with steroid exposure (31) while simultaneously maximizing efficacy. In addition, our data demonstrate that STAT5B was primarily responsible for the upregulation of BCL-2 expression in this context, consistent with previous reports demonstrating that knockdown of STA-T5A is insufficient to modulate IL-7-mediated regulation of BCL-2 expression (11). Interestingly, this is also consistent with the finding that activating mutations in STAT5B, but not STAT5A, commonly occur in T-ALL (1).…”

“…One critical endogenous factor in the T-ALL microenvironment is the cytokine IL-7. In addition to promoting the survival and differentiation of developing thymocytes (10), the IL-7 receptor/ JAK/STAT5 (IL-7R/JAK/STAT5) signaling pathway contributes to T-ALL pathogenesis and disease maintenance (11)(12)(13). We previously demonstrated that over half of primary treatment-naive T-ALL patient samples were intrinsically resistant to the glucocorticoid dexamethasone (DEX) when cultured in the presence of IL-7.…”

Flip the coin: IL-7 and IL-7R in health and disease

“…3e; downregulation as well as Bcl-2 upregulation 73,74 . In agreement, IL-7-mediated Bcl-2 upregulation in T-ALL cells appears to be STAT5-independent 75 -again in opposition to the fact that IL-7mediated STAT5 activation in naïve T-cells associates with survival 71 , suggesting that IL-7-…”

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

“…Previous report suggested that BCR-ABL oncogene mimics pre-BCR signaling by activating STAT5 on one hand and repressing BCL6 expression on the other hand 7 . STAT5 was also shown to directly downregulate BCL6 expression in response to IL7 stimulation 43 . This is in agreement with our data showing that BCR-ABL1 transformation downregulates the transcription repressor BCL6.…”