Targeting STAT5 or STAT5-Regulated Pathways Suppresses Leukemogenesis of Ph+ Acute Lymphoblastic Leukemia

Abstract

Combining standard cytotoxic chemotherapy with BCR-ABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCR-ABL1-dependent and -independent mechanisms, prognosis remains poor. The STAT5 transcription factor is activated by BCR-ABL1 and by JAK2-dependent cytokine signaling; therefore, inhibiting its activity could address both mechanisms of resistance in Ph+ ALL. We show here that genetic and pharmacologic inhibition of STAT5 activity suppresses cell growth, induces apoptosis, and inhibits leukemogenesis of Ph+ cell lines and patient-derived newly diagnosed and relapsed/TKI-resistant Ph+ ALL cells and in mouse models. STAT5 silencing decreased expression of the growth-promoting PIM-1 kinase, the apoptosis inhibitors MCL1 and BCL2, and increased expression of proapoptotic BIM protein. The resulting apoptosis of STAT5-silenced Ph+ BV173 cells was rescued by silencing of BIM or restoration of BCL2 expression. Treatment of Ph+ ALL cells, including samples from relapsed/refractory patients, with the PIM kinase inhibitor AZD1208 and/or the BCL2 family antagonist Sabutoclax markedly suppressed cell growth and leukemogenesis and in mice. Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease. Suppression of STAT5 by BCL2 and PIM kinase inhibitors reduces leukemia burden in mice and constitutes a new potential therapeutic approach against Ph+ ALL, especially in tyrosine kinase inhibitor-resistant disease. .

Balancing STAT Activity as a Therapeutic Strategy

“…Deletion of STAT5 prevents transformation by the Abl oncogene, thereby preventing leukemia development [228]. Genetic and pharmacologic inhibition of STAT5 activity decreases expression of apoptosis inhibitors MCL1 and BCL2 and inhibits leukemogenesis of BCR-ABL1+ acute lymphoblastic leukemia (ALL), both in cell lines and newly diagnosed and relapsed/TKI-resistant ALL patients [229]. Likewise, a new, STAT5 inhibitor suppressed the proliferation of human acute myeloid leukemia (AML) cell lines and primary FLT3-ITD+ AML patient cells [74].…”

Involvement of STAT5 in Oncogenesis

“…Moreover, phosphorylated STAT5 could interact with PI3K to activate the PI3K/Akt pathway, enhancing cell growth [ 103 ]. On the other hand, the inhibition of STAT5 reduces anti-apoptotic proteins, Bcl-2 and MCL-1, as well as increasing pro-apoptotic protein, Bim, expression [ 104 ]. Therefore, constitutive STAT5 activation in leukaemia can result in increased cell transformation, proliferation, survival, drug resistance to imatinib and the inhibition of apoptosis [ 80 , 82 , 83 ].…”

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

“…The STAT5 target gene PIM2 contributes to imatinib resistance and its inhibition sensitized LSCs towards pharmacological treatment [163]. Suppression of the STAT5 target genes PIM1 and BCL2 (PIM kinase inhibitor AZD1208 and BCL2 antagonist Sabutoclax) induced apoptosis in BCR–ABL + ALL cells [164].…”

“…The sterical confirmation of STAT5B N642H hinders AC-4-130 binding [175], making it not applicable for targeted treatment of patients who carry STAT5B N642H . Another example for a STAT5A/B SH2 domain inhibitor, IST5-002, blocked phosphorylation and nuclear translocation of STAT5A/B in BCR–ABL + in vitro and in vivo systems [164,176]. Via a virtual compound library screening approach and further structural adaptions, the first STAT5A SH2 domain inhibitor was identified, showing a modest reduction of pYSTAT5A levels in BCR–ABL + cells [177].…”