Identification of somatic JAK1 mutations in patients with acute myeloid leukemia

Zhang, Xiang; Zhao, Yu; Mitaksov, Vesselin; Fremont, Daved H.; Kasai, Yumi; Molitoris, AnnaLynn; Ries, Rhonda E.; Miner, Tracie L.; McLellan, Michael D.; DiPersio, John F.; Link, Daniel C.; Payton, Jacqueline E.; Graubert, Timothy A.; Watson, Mark A.; Shannon, William D.; Heath, Sharon E.; Nagarajan, Rakesh; Mardis, Elaine R.; Wilson, Richard K.; Ley, Timothy J.; Tomasson, Michael H.

doi:10.1182/blood-2007-05-090308

Cited by 88 publications

(77 citation statements)

References 21 publications

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“…3,4,[8][9][10] Thus, it has been shown that JAK pseudokinase domains are auto-inhibitory and keep the kinase domain inactive until receptor dimerization stimulates transition to an active state. 11 Molecular analysis of deregulated JAK/STAT signaling has provided a novel rationale for treating human cancers using targeted inhibition of JAK kinases.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

et al. 2015

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Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphomaThe malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are starting to be identified. Recent evidence suggests that disturbances in specific intracellular signaling pathways, such as RAS-MAPK, TCR-PLCG1-NFAT and JAK-STAT, can play an essential role in the pathogenesis of CTCL.1,2 Our group previously reported a network of somatic mutations affecting genes with potential to affect critical Tcell signaling pathways in CTCL patients. 1 As part of our findings we detected a number of mutations potentially affecting JAK/STAT signaling. These findings were recently confirmed by an independent group, suggesting that mutations in this pathway may contribute as disease mechanisms in CTCL.3 Deregulated JAK/STAT signaling is involved in many types of cancer. In fact, somatically acquired genetic alterations of JAK or STAT genes that induce aberrant activation of downstream signaling, via STAT phosphorylation, have been reported in some human hematologic malignancies including T-cell lymphomas. 4,5 We decided to explore JAK/STAT signaling as part of an intricate network of malignant signaling that controls the pathogenesis of CTCL, on the basis of the following evidence: (i) we had detected mutations in the pseudokinase domain of JAK1 and JAK3 in two of 11 patients and one cell line; (ii) we had also found several mutations that can directly (i.e., IL6S/T) or indirectly (i.e., TRAF6, RELB and CARD11) activate JAK/STAT signaling; and (iii) activated STAT3 had been detected in a large proportion of patients with advanced CTCL. 6,7 To explore the mutational status of JAK genes in a larger cohort of human CTCL patients' samples and cell lines, two independent state-of-the-art ultrasequencing approaches were used: a targeted gene-enrichment kit (HaloPlex) coupled to Ion-PGM (Life Technologies) sequencing, and a specific polymerase chain reactionbased amplification protocol targeting the pseudokinase domains of JAK1, JAK2 and JAK3 genes (hereafter, referred to as PsTKd-PCR), followed by specific indexing and sequencing with MiSeq (Illumina; see the Online Supplementary Methods for details). These are two highly sensitive methods that can enable the detection of mutations even present at low frequencies in neoplastic cells or in minority clones which may be found in CTCL samples. Thus, taken together, the data from our series (including those already described by Vaqué et al. © F e r r a t a S t o r t i F o u n d a t i o nthe pseudokinase domain of JAK proteins, a finding that is consistent with the results of other research groups that have found somatic mutations in the same domain of JAK1 and JAK3 kinases in prolymphocytic leukemia, other T-cell leukemias including CTCL and various human malignancies. 3,4,[8][9][10] Thus, it has been shown that JAK pseudokinase domains are auto-inhibitory and keep the kinase domain inactive until receptor dimerization stimulates transition to an a...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

et al. 2015

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“…Cytogenetic abnormalities associated with extramedullary AML include MLL rearrangement, t(8:21), inversion 16, 11q abnormalities, and mutations of nucleophosmin (NPM) 1 (9,10). Mutations in the JAK, TET2, and TP53 found in this case have been described in the pathogenesis of AML, but not in relation to MS (9)(10)(11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 94%

Acute myeloid leukemia masquerading as hepatocellular carcinoma

Abu‐Zeinah

Weisman

Ganesh

et al. 2016

J. Gastrointest. Oncol.

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A 64-year-old Caucasian man developed progressive fatigue, abdominal distension, and 25 pounds weight loss (10% of his body weight) over a month period. His outpatient workup included an abdominal ultrasound that revealed a large liver mass. Magnetic resonance imaging confirmed a solitary 11 cm mass with central necrosis within segments 6 and 7 of the right hepatic lobe. The patient had no history of excessive alcohol intake, viral hepatitis, steatosis or liver cirrhosis. An alpha-fetoprotein (AFP) level was 7.9 ng/mL. Given the features of the liver mass on imaging, and despite the lack of cirrhosis and elevated AFP, a diagnosis of hepatocellular carcinoma (HCC) was presumed and the patient was considered for hepatobiliary surgery.In the interim, the patient had rapid functional decline. He was admitted for fever (39 ℃), confusion and back pain. The physical exam was notable for altered mental status and flapping tremor without meningismus, lower extremity weakness or focal neurologic findings. Laboratory studies revealed a white blood count (WBC) of 3.0×10 3 /µL, Abstract: Hepatocellular carcinoma (HCC) is often diagnosed on the basis of high quality imaging without a biopsy in the cirrhotic liver. This is a case of a 64-year-old Caucasian man with no history of liver disease or cirrhosis that presented with fatigue, weight loss, and abdominal distension and was found to have a large, isolated liver mass with arterial enhancement and portal venous washout on triple-phase computed tomography (CT) suspicious for HCC. The patient was initially referred for a surgical evaluation.Meanwhile, he developed fevers, pancytopenia, and worsening back pain, and a subsequent spinal MRI revealed a heterogeneous bone marrow signal suspicious for metastatic disease. A bone marrow biopsy that followed was diffusely necrotic. A core biopsy of the patient's liver mass was then performed and was diagnostic of acute monocytic-monoblastic leukemia. Findings from peripheral flow cytometry and a repeat bone marrow biopsy were also consistent with this diagnosis, and induction chemotherapy with cytarabine and idarubicin was initiated. This case describes a rare presentation of myeloid sarcoma (MS) as an isolated, hypervascular liver mass that mimics HCC in its radiographic appearance. Due to the broad differential for a liver mass, a confirmatory biopsy should routinely be considered prior to surgical intervention.

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“…113 However, Xiang et al 114 identified two novel JAK1 mutations (T478S, V623A) in two out of 94 patients with AML. These mutations did not transform Ba/F3 cells to growth factor independence but were shown to activate multiple downstream pathways in vitro.…”

Section: Jak2 Mutationsmentioning

confidence: 99%

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

et al. 2008

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Identification of somatic JAK1 mutations in patients with acute myeloid leukemia

Cited by 88 publications

References 21 publications

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

Acute myeloid leukemia masquerading as hepatocellular carcinoma

Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders

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