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Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.

ABSTRACT: Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK-Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment.

SUBMITTER: Naka K

PROVIDER: S-EPMC4560789 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.

Naka Kazuhito K Jomen Yoshie Y Ishihara Kaori K Kim Junil J Ishimoto Takahiro T Bae Eun-Jin EJ Mohney Robert P RP Stirdivant Steven M SM Oshima Hiroko H Oshima Masanobu M Kim Dong-Wook DW Nakauchi Hiromitsu H Takihara Yoshihiro Y Kato Yukio Y Ooshima Akira A Kim Seong-Jin SJ

Nature communications 20150820

Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher lev ...[more]

PMID: 26289811

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Project description:BackgroundThe financial burden of medical expenses has been increasing for cancer patients. We investigated the relationship between household income and financial burden among patients with chronic myelogenous leukaemia (CML) who have been treated with imatinib.MethodsA questionnaire was distributed to 1200 patients between May and August 2009. We retrospectively surveyed their household incomes, out-of-pocket medical expenses, final co-payments after refunds, and the perceived financial burden of their medical expenses in 2000, 2005 and 2008.ResultsA total of 577 patients completed the questionnaire. Their median age was 61?years (range, 15-94). A financial burden was felt by 41.2?% (28 of 68) of the patients treated with imatinib in 2000, 70.8?% (201 of 284) in 2005, and 75.8?% (400 of 528) in 2008. Overall, 182 patients (31.7?%) considered its discontinuation because of the financial burden and 15 (2.6?%) temporarily stopped their imatinib prescription. In 2000, 2005 and 2008, the patients' median annual household incomes were 49,615 US Dollars (USD), 38,510 USD and 36,731 USD, respectively, with an average currency exchange rate of 104 Yen/USD in 2008. Their median annual out-of-pocket expenses were 11,548, 12,067 and 11,538 USD and their median final annual co-payments were 4,375, 4,327 and 3,558 USD, respectively. Older patients (OR?=?0.96, 95?% CI: 0.95-0.98, p???0.0001 for 1-year increments), and patients with higher household incomes (OR?=?0.92, 95?% CI: 0.85-0.99, p?=?0.03 for 10,000 USD-increments) were less likely to have considered discontinuing their imatinib treatment. Conversely, patients with higher annual final co-payments (OR?=?2.21, 95?% CI: 1.28-4.28, p?=?0.004 for 10,000 USD-increments) were more likely to have considered discontinuing their imatinib treatment.ConclusionsThe proportion of CML patients who sensed a financial burden increased between 2000 and 2008. During this period, their annual incomes fell by 13,000 USD, although their medical expenses did not change. Financial support for patients being treated with expensive drugs remains a major problem in Japan.

Dataset Information

Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.

Publications

Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells.

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