SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function

Abstract

Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long-term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML.

SOCS2 Controls Proliferation and Stemness of Hematopoietic Cells under Stress Conditions and Its Deregulation Marks Unfavorable Acute Leukemias

“…In CML patients, upregulated SOCS2 was found in CD34 þ cells during the transition from the chronic phase to the blast phase and has been associated with poor prognosis (40,41). In contrast, a mouse model of BCR/ABL1-induced CML shows the same incidence regardless SOCS2 deficiency (25). However, these data cannot be considered conclusive given that such model is characterized by a short latency and rapid progression, representing a suboptimal setting to appreciate any potential phenotype related with SOCS2 effects.…”

“…This was related with the composition of the LKS pool that in Socs2 À/À bone marrow chimeras was characterized by higher ST-HSC and MPP but reduced LT-HSC frequencies. SOCS2 is overexpressed in primitive HSC (13-16) compared with more differentiated populations, both in human (13-16 and mouse (22,25), suggesting that basal SOCS2 expression could contribute to stemness maintenance. Nevertheless, Hansen and colleagues (25) published that Socs2-deficient mice had normal reconstitution capacity in primary and secondary competitive BMT experiments.…”

“…SOCS2 is overexpressed in primitive HSC (13-16) compared with more differentiated populations, both in human (13-16 and mouse (22,25), suggesting that basal SOCS2 expression could contribute to stemness maintenance. Nevertheless, Hansen and colleagues (25) published that Socs2-deficient mice had normal reconstitution capacity in primary and secondary competitive BMT experiments. Our kinetic analysis of Socs2 expression following the bone marrow myeloablation (BMT or 5-FU) clearly indicated that SOCS2 overexpression and SOCS2-negative regulation of STAT5 are transient and occur within 1 day after myeloablative treatment.…”

t(8;9)(p22;p24)/PCM1-JAK2 Activates SOCS2 and SOCS3 via STAT5

“…While also a JAK-STAT signalling inhibitor, SOCS2 lacks the KIR domain found in SOCS3, proferring an explanation for their diverse modes of action. Although, Schultheis et al [39] reported SOCS2 activation in CML, Hansen et al [40] have shown its redundance for generation of CML in a BCR-ABL1 driven mouse model, implying that feedback regulation by SOCS2 is deficient in this setting. Underlying these discrepancies may be that SOCS2 inhibits STAT5 induced by growth hormone signalling at lower transcription levels, but at high levels stimulates STAT5 [41].…”

Natural course and biology of CML

“…Interestingly, whilst JAK2 is upstream of STAT5, it was reported that deletion of JAK2 was not essential for myeloid (but was required for lymphoid) leukaemia in BCR-ABL1 mouse models [54]. It was proposed that BCR-ABL1 may directly activate STAT5 [54] and bypass endogenous regulation by JAK2 to promote leukaemogenesis [55,56]. Nevertheless, JAK inhibitors exhibit efficacy against primary CML cells, including TKI-resistant cells [57], and recent work suggests that JAK-signalling is important for stem cell biology (discussed later).…”