STAT5: From Pathogenesis Mechanism to Therapeutic Approach in Acute Leukemia

Mohammad Shahjahani, PhD; Amirreza Abroun, MSc; Najmaldin Saki, PhD; Seyed Mohammad Bagher Mohammadi, MSc; Hadi Rezaeeyan, PhD

Disclosures

Lab Med. 2020;51(4):345-351.

Conclusion

Although much progress has been made in the identification of molecular pathways in Ph-positive ALL cells to design appropriate treatments, some patients still do not show complete response to common treatments, and disease relapse remains a challenge. It seems that the proliferation of leukemia cells and their refractoriness to apoptosis are the main factors of resistance to chemotherapy. In contrast, according to the aforementioned content, STAT5 is a vital factor in the progression and prognosis of acute leukemia (especially ALL) through its undeniable role in the proliferation of leukemic cells and the inhibition of their apoptosis, as well as inducing hTERT (a catalytic unit of telomerase complex). We hypothesize that targeting STAT5 in patients not only suppresses the proliferation of Ph-positive ALL cells but also makes these cells sensitive to chemotherapy via decreasing the expression of hTERT. Confirmation of this possibility will require further studies in the future.

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Abbreviations
T-ALL, T-cell acute lymphoblastic leukemia; IL, interleukin; JAK/STAT, Janus kinase/signal transducer and activator of transcription; STAT5, signal transducer and activator of transcription 5; RUNX3, Runt-related transcription factor; T-regs, regulatory T cells; FOXP3, forkhead box P3; CLP, common lymphocyte progenitor; Ph-positive, presence of the Philadelphia chromosome; CML, chronic myeloid leukemia; Src, SRC proto-oncogene, nonreceptor tyrosine kinase; Lyn, LYN proto-oncogene; BCR-ABL1, breakpoint cluster region protein–Abelson murine leukemia viral oncogene homolog 1; BCL-2, B-cell lymphoma 2; mTOR, mammalian target of rapamycin; Raf, proto-oncogene serine/threonine-protein kinase; MEK, mitogen-activated protein kinase; GAB2, Grb-associated binder-2; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; mTORC1, mammalian target of rapamycin complex 1; S6K, S6 kinase; 4E-BP-1, 4E–binding protein–1; MDM2, mouse double minute 2 homolog; BLNK, B-cell linker; C-myc, MYC proto-oncogene; HES1, hairy/enhancer of split; ADP, adenosine 5′-diphosphate; PARP1, poly adenosine 5′-diphosphate ribose polymerase 1; CD, cluster of differentiation; AML, acute myeloid leukemia; FLT3, FMS-like tyrosine kinase 3; MAPK/ERK, extracellular regulated mitogen-activated protein kinase; MCL-1, MCL1 apoptosis regulator; GM-CSF, granulocyte-macrophage colony-stimulating factor; AXL, AXL receptor tyrosine kinase; hTR, human telomerase RNA template; HSP90, heat shock protein 90; MDR1, multiple drug resistance 1; P-gp, P-glycoprotein; ATP, adenosine triphosphate; MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species; HSCs, hematopoietic stem cells; ETC1, electron transport chain complex 1; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; AKT, serine/threonine kinase; Nrf2, nuclear factor erythroid 2–related factor 2; MRP-1, multidrug resistance–associated protein 1; EPHX1, microsomal epoxide hydrolase 1; TUG1, taurine upregulated gene 1; miR-34a, microRNA 34a; EIF4E, eukaryotic translation initiation factor 4E; ALL, acute lymphoblastic leukemia; STAT5B, signal transducer and activator of transcription 5; Pax5, paired box protein 5; B-All, B-cell acute lymphocytic leukemia; JAK2, Janus kinase 2/signal transducer and activator of transcription; BACH2, BTB domain and CNC homolog 2; ND, not determined; BCL-6, B-cell lymphoma 6; EGR, early growth response protein 1; FBXW7, F-box/WD repeat-domain-containing protein 7; RUNX1, Runt-related transcription factor 1

Table 1. Factors Affecting Drug Resistance in Leukemia
Factor	Disease	Mechanism	Reference
ETC1	AML	Increased BCL2 and inhibition of apoptosis	⁴⁶
FLT3-ITD	AML	Through JAK/STAT and AKT/mTOR pathways, causes proliferation of cells	⁴⁷
Nrf2	AML	Through PI3K/AKT and MRP-1, protein resistance to chemotherapy	⁴⁸
EPHX1	AML	Increased cell viability and resistance to apoptosis by BCL2	⁴⁹
TUG1	AML	Suppressing miR-34a resistance to chemotherapy	⁵⁰
EIF4E protein	ALL	Increased proliferation of leukemia cell	⁵¹

ETC1, electron transport chain complex 1; AML, acute myeloid leukemia; BCL-2, B-cell lymphoma 2; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; JAK-STAT, Janus kinase/signal transducer and activator of transcription; AKT, serine/threonine kinase; mTOR, mammalian target of rapamycin; Nrf2, nuclear factor erythroid 2–related factor 2; MRP-1, multidrug resistance–associated protein 1; EPHX1, microsomal epoxide hydrolase 1; TUG1, taurine upregulated gene 1; miR-34a, microRNA 34a; EIF4E, eukaryotic translation initiation factor 4E; ALL, acute lymphoblastic leukemia.

Table 2. Summary of Gene Mutations in Acute Lymphocytic Leukemia
Factor	Mutation	Mutation Type	Location	Lineage	Effect	Prognosis	Reference
STAT5B	Gain of function	Missense	N642H	T-ALL	Enhances expression of BCL2 and PIM1 and prevents apoptosis	Poor	⁵⁹
					Enhances relapse after treatment
Pax5	Loss of function	Missense	C547G>A	B-ALL	Enhances activation of JAK2/STAT pathway and leads to proliferation of leukemia cells	Poor	⁶⁰
BACH2	Loss of function	ND	ND	B-ALL	Reduces the expression of TP53 and enhances expression of BCL-6	Poor	⁶¹
FLT3	Gain of function	Point mutation	D835/I836	ND	Enhances phosphorylation of downstream targets such as STAT5 and leads to proliferation of leukemic cells	Poor	⁶²
EGR-1	Loss of function	Deletion	ND	T-ALL	Reduces self-renewal of leukemic cell leading to responsiveness to treatment	Good	⁶³
FBXW7	Loss of function	Missense	1542C>T	T-ALL	Leads to activation of Notch pathway and differentiation of leukemic cells	Good	^56,64
RUNX1	Loss of function	Deletion	ND	T-ALL	Inhibits the differentiation of T-cells	Poor	⁶⁵

STAT5B, signal transducer and activator of transcription 5; T-ALL, T-cell acute lymphocytic leukemia; BCL-2, B-cell lymphoma 2; Pax5, paired box protein 5; B-All, B-cell acute lymphocytic leukemia; JAK2, Janus kinase 2/signal transducer and activator of transcription; BACH2, BTB domain and CNC homolog 2; ND, not determined; BCL-6, B-cell lymphoma 6; FLT3, Fms like tyrosine kinase 3; EGR, early growth response protein 1; FBXW7, F-box/WD repeat-domain-containing protein 7; RUNX1, Runt-related transcription factor 1.