| Note | |
| | |
| Entity | Acute lymphoblastic leukemia T cell type (T-ALL) and Acute lymphoblastic leukemia B cell type (B-ALL) |
| Prognosis | JAK1 mutations are associated with advanced age, poor response to therapy and overall prognosis (Flex et al., 2008). |
| Oncogenesis | Somatic JAK1 mutations occur in T cell acute lymphoblastic leukemia (ALL). These mutations seem to be more frequent among adult T-ALL patients, but the frequency varies between studies: 8/38 (21.0%; adult; Flex et al., 2008), 1/49 (2.0%; children; Flex et al., 2008), 2/11 (27.3%; adult; Jeong et al., 2008), 4/108 (3.7%; adult; Asnafi et al., 2009). These mutations represent gain of function mutations that participate in the leukemogenic process by inducing the constitutive activation of the JAK-STAT pathway.
Table 1: Somatic mutations in JAK1 found in T-ALL patients.
| Amino acid substitution | Proof of hyperactivity | domain | reference | | S512L | | SH2 | Flex et al., 2008 | | A634D | Yes | Pseudokinase | Flex et al., 2008 | | Y652H | | Pseudokinase | Asnafi et al., 2009 | | V658F | Yes | Pseudokinase | Jeong et al., 2008 | | R724H | Yes | Pseudokinase | Flex et al., 2008 | | R724Q | | Pseudokinase | Asnafi et al., 2009 | | T782M | | Pseudokinase | Jeong et al., 2008 | | L783F | | Pseudokinase | Jeong et al., 2008 | | R879S | | Kinase | Flex et al., 2008 | | R879C | Yes | Kinase | Flex et al., 2008 | | R879H | | Kinasee | Flex et al., 2008 | JAK1 mutations were found in 3 B-cell ALL samples after the resequencing of 173 B-ALL (Flex et al., 2008) and in 3 samples after the resequencing of 187 high risk childhood B-ALL (Mullighan et al., 2009). No mutations were found after the resequencing of 69 B-ALL (Jeong et al., 2008).
Table 2: Somatic mutations in JAK1 found in B-ALL patients.
| Amino acid substitution | Proof of hyperactivity | domain | reference | | K204M | | FERM | Flex et al., 2008 | | L624_R629>W | Yes | Pseudokinase | Mullighan et al., 2009 | | A634D | Yes | Pseudokinase | Flex et al., 2008 | | S646F | Yes | Pseudokinase | Mullighan et al., 2009 | | L653F | | Pseudokinase | Flex et al., 2008 | | V658F | Yes | Pseudokinase | Mullighan et al., 2009 | | R724H | Yes | Pseudokinase | Flex et al., 2008 | JAK1 mutants induce the activation of different cytokine-receptor complexes like the IL-9 receptor or the IL-2 receptor, that will induce the constitutive activation of the JAK-STAT pathway. |
| | |
| | |
| Entity | Acute myeloid leukemia (AML) |
| Oncogenesis | JAK1 mutations were found in two AML samples after the resequencing of 94 AML (Xiang et al., 2008) and in one AML sample after the resequencing of 105 AML.
Table 3: Somatic mutations in JAK1 found in AML samples.
| Amino acid substitution | Proof of hyperactivity | domain | reference | | T478S | | SH2 | Xiang et al., 2008 | | V623A | | Pseudokinase | Xiang et al., 2008 | | V658F | Yes | Pseudokinase | Jeong et al., 2008 | |
| | |
| | |
| Entity | Hepatocellular carcinoma |
| Oncogenesis | JAK1 mutations were found in one hepatocellular carcinoma sample after the screening of 84 hepatocellular carcinoma.
Table 4: Somatic mutations in JAK1 found in hepatocellular carcinomas.
| Amino acid substitution | Proof of hyperactivity | domain | reference | | Q644H;V645F | | Pseudokinase | Xie et al., 2009 | |
| | |
| | |
| Entity | Breast cancer |
| Oncogenesis | JAK1 mutation was found in a breast cancer sample after the resequencing of 90 breast cancers.
Table 5: Somatic mutations in JAK1 found in breast cancer samples.
| Amino acid substitution | Proof of hyperactivity | domain | reference | | H647Y | | Pseudokinase | Jeong et al., 2008 | |
| | |
| | |
| Entity | Non-small cell lung cancer |
| Oncogenesis | JAK1 mutation was found in a non-small cell lung cancer sample after the resequencing of 47 non-small cell lung cancer samples.
Table 6: Somatic mutations in JAK1 found in non-small cell lung cancer samples.
| Amino acid substitution | Proof of hyperactivity | domain | reference | | P782M | | Pseudokinase | Jeong et al., 2008 | |
| | |
| JAK1 mutations are not frequent events in adult T-ALL: a GRAALL study. |
| Asnafi V, Le Noir S, Lhermitte L, Gardin C, Legrand F, Vallantin X, Malfuson JV, Ifrah N, Dombret H, Macintyre E. |
| Br J Haematol. 2009 Sep 18. [Epub ahead of print] |
| PMID 19764985 |
| |
| Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. |
| Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F, Martinelli S, Fragale A, Sanchez M, Tavolaro S, Messina M, Cazzaniga G, Camera A, Pizzolo G, Tornesello A, Vignetti M, Battistini A, Cave H, Gelb BD, Renauld JC, Biondi A, Constantinescu SN, Foa R, Tartaglia M. |
| J Exp Med. 2008 Apr 14;205(4):751-8. Epub 2008 Mar 24. |
| PMID 18362173 |
| |
| Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers. |
| Hornakova T, Staerk J, Royer Y, Flex E, Tartaglia M, Constantinescu SN, Knoops L, Renauld JC. |
| J Biol Chem. 2009 Mar 13;284(11):6773-81. Epub 2009 Jan 12. |
| PMID 19139102 |
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| Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. |
| Jeong EG, Kim MS, Nam HK, Min CK, Lee S, Chung YJ, Yoo NJ, Lee SH. |
| Clin Cancer Res. 2008 Jun 15;14(12):3716-21. |
| PMID 18559588 |
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| JAK kinases overexpression promotes in vitro cell transformation. |
| Knoops L, Hornakova T, Royer Y, Constantinescu SN, Renauld JC. |
| Oncogene. 2008 Mar 6;27(11):1511-9. Epub 2007 Sep 17. |
| PMID 17873904 |
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| JAK mutations in high-risk childhood acute lymphoblastic leukemia. |
| Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, Tasian SK, Loh ML, Su X, Liu W, Devidas M, Atlas SR, Chen IM, Clifford RJ, Gerhard DS, Carroll WL, Reaman GH, Smith M, Downing JR, Hunger SP, Willman CL. |
| Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8. Epub 2009 May 22. |
| PMID 19470474 |
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| Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. |
| Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ. |
| Blood. 2008 May 1;111(9):4797-808. Epub 2008 Feb 12. |
| PMID 18270328 |
| |
| Identification of somatic JAK1 mutations in patients with acute myeloid leukemia. |
| Xiang Z, Zhao Y, Mitaksov V, Fremont DH, Kasai Y, Molitoris A, Ries RE, Miner TL, McLellan MD, DiPersio JF, Link DC, Payton JE, Graubert TA, Watson M, Shannon W, Heath SE, Nagarajan R, Mardis ER, Wilson RK, Ley TJ, Tomasson MH. |
| Blood. 2008 May 1;111(9):4809-12. Epub 2007 Dec 26. |
| PMID 18160671 |
| |
| Mutational analysis of JAK1 gene in human hepatocellular carcinoma. |
| Xie HJ, Bae HJ, Noh JH, Eun JW, Kim JK, Jung KH, Ryu JC, Ahn YM, Kim SY, Lee SH, Yoo NJ, Lee JY, Park WS, Nam SW. |
| Neoplasma. 2009;56(2):136-40. |
| PMID 19239328 |
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