Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells

Abstract

Key Points• JAK/STAT signaling is constitutively increased in AML stem and progenitor cells.• JAK2 inhibition significantly inhibits AML but not normal stem cell growth.Acute myeloid leukemia (AML) is sustained by small populations of leukemia stem cells (LSCs) that can resist available treatments and represent important barriers to cure. Although previous studies have shown increased signal transducer and activator of transcription (STAT)3 and STAT5 phosphorylation in AML leukemic blasts, the role of Janus kinase (JAK) signaling in primary AML compared with normal stem cells has not been directly evaluated. We show here that JAK/STAT signaling is increased in LSCs, particularly from high-risk AML. JAK2 inhibition using small molecule inhibitors or interference RNA reduced growth of AML LSCs while sparing normal stem cells both in vitro and in vivo. Increased JAK/STAT activity was associated with increased expression and altered signaling through growth factor receptors in AML LSCs, including receptor tyrosine kinase c-KIT and FMS-related tyrosine kinase 3 (FLT3). Inhibition of c-KIT and FLT3 expression significantly inhibited JAK/STAT signaling in AML LSCs, and JAK inhibitors effectively inhibited FLT3-mutated AML LSCs. Our results indicate that JAK/STAT signaling represents an important signaling mechanism supporting AML LSC growth and survival. These studies support continued evaluation of strategies for JAK/STAT inhibition for therapeutic targeting of AML LSCs. (Blood. 2014;123(18):2826-2837

JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo

“…We speculate that in CML SPCs, the prior expression of BCR-ABL may alter signaling networks such that cells are dependent on higher levels of GFs signaling activity, possibly due to upregulation or enhanced activity of cytokine receptors as shown already in both CML 53,54 and acute myeloid leukemia models. 55 Upon BCR-ABL inhibition, these cells may therefore be dependent on higher levels of GF-mediated JAK2/STAT5 activation for continued viability as compared with normal cells. Moreover, it is reassuring that RUX has been used as a single agent for the treatment of patients with myelofibrosis, 30,31 with no severe BM toxicity experienced, especially for patients with good BM reserve, which is the prevailing situation in CP CML patients with minimal residual disease on TKI.…”

An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers

“…For example, treatment with AZD1480, an ATP-competitive inhibitor of JAK kinases, reduced leukemic engraftment in xenograft studies of a small number of AML samples (n ¼ 7; ref. 34). In vitro analysis of 48 AML samples demonstrated inhibition of both pSTAT3 and pSTAT5 in the phenotypically defined CD34 þ LSC/progenitor blast population, but the degree of inhibition was quite variable (0%-100%).…”

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

“…As multiple TKs play a critical role in STAT3/ STAT5 phosphorylation and activation (45), there is substantial interest to target TKs upstream of STAT3/STAT5. FLT3-ITD is the most common molecular aberration in AML, activates primarily pSTAT5 signaling, and confers poor prognosis (24,46). A variety of TKIs targeting FLT3 activity have been evaluated in clinical phase I/II studies in relapsed/refractory AML patients (47).…”

“…þ AML LSCs compared with normal cord blood or peripheral blood stem cells, suggesting that JAK/STAT signaling supports AML LSC growth and survival (24). Furthermore, pSTAT5 signaling is increased and essential for the maintenance of leukemic stem/progenitor cells (25).…”