bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2019-64-4-424-435bloodjour-163Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESИЗМЕНЕНИЯ В КЛЕТКАХ-ПРЕДШЕСТВЕННИЦАХ СТРОМАЛЬНОГО МИКРООКРУЖЕНИЯ КОСТНОГО МОЗГА БОЛЬНЫХ ХРОНИЧЕСКИМ МИЕЛОЛЕЙКОЗОМ В ДЕБЮТЕ ЗАБОЛЕВАНИЯ И В ХОДЕ ЛЕЧЕНИЯCHANGES IN STROMAL PROGENITOR CELLS DERIVED FROM BONE MARROW IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKAEMIA AT THE ONSET OF THE DISEASE AND DURING TREATMENThttps://orcid.org/0000-0001-6591-3183ПетинатиН. А.PetinatiN. A.

Петинати Наталия Арнольдовна*, кандидат медицинских наук, старший научный сотрудник лаборатории физиологии кроветворения

Natalya A. Petinati, Cand. Sci. (Med.), Senior Researcher, Laboratory for Physiology of Hematopoiesis

loel@mail.ruhttps://orcid.org/0000-0003-1189-0283ШипуноваИ. Н.ShipunovaI. N.

Шипунова Ирина Николаевна, кандидат биологических наук, старший научный сотрудник лаборатории физиологии кроветворения

Irina N. Shipunova, Cand. Sci. (Biol.), Senior Researcher, Laboratory for Physiology of Hematopoiesis

iranifontova@yandex.ruhttps://orcid.org/0000-0003-0215-9085БигильдеевА. Е.BigildeevA. E.

Бигильдеев Алексей Евгеньевич, доктор биологических наук, старший научный сотрудник лаборатории физиологии кроветворения

Alexey E. Bigildeev, Dr. Sci. (Biol.), Senior Researcher, Laboratory for Physiology of Hematopoiesis

bigildeev_ae@gmail.ruhttps://orcid.org/0000-0002-1559-9381СацН. В.SatsN. V.

Сац Наталья Владимировна, кандидат биологических наук, старший научный сотрудник лаборатории физиологии кроветворения

Natalya V. Sats, Cand. Sci. (Biol.), Senior Researcher, Laboratory for Physiology of Hematopoiesis

nsats@yandex.ruhttps://orcid.org/0000-0001-6423-1789ЧелышеваЕ. Ю.ChelyshevaE. Yu.

Челышева Екатерина Юрьевна, кандидат медицинских наук, старший научный сотрудник научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

Ekaterina Yu. Chelysheva, Cand. Sci. (Med.), Senior Researcher, Research and Advisory Department of Chemotherapy of Myeloproliferative Diseases

denve@bk.ruhttps://orcid.org/0000-0001-5393-0816ШуховО. А.ShukhovO. A.

Шухов Олег Александрович, кандидат медицинских наук, научный сотрудник отделения, врач-гематолог 

тел.: +7(495)612-16-36

Oleg A. Shukhov, Cand. Sci. (Med.), Researcher, Hematologist

tel.: +7(495)612-16-36

shuhov@list.ruhttps://orcid.org/0000-0001-5730-2593ПетроваА. Н.PetrovaA. N.

Петрова Анна Николаевна, аспирант научно-консультативного отделения химиотерапии миелопролиферативных заболеваний, врач-гематолог

Anna N. Petrova, Postgraduate Researcher, Scientific Advisory Department for Chemotherapy of Myeloproliferative Disorders, Hematologist

ap996@mail.ruhttps://orcid.org/0000-0001-9947-2371ТуркинаА. Г.TurkinaA G.

Туркина Анна Григорьевна, доктор медицинских наук, профессор, руководитель научно-консультативного отделения химиотерапии миелопролиферативных заболеваний

Anna G. Turkina, Dr. Sci. (Med.), Prof., Head of the Research and Advisory Department of Chemotherapy of Myeloproliferative Diseases

turkianna@yandex.ruhttps://orcid.org/0000-0002-7150-0403ДризеН. И.DrizeN. I.

Дризе Нина Иосифовна, доктор биологических наук, заведующая лабораторией физиологии кроветворения

Nina I. Drize, Dr. Sci. (Biol.), Head of the Laboratory for Physiology of Hematopoiesis

ndrize@yandex.ruФГБУ «Национальный медицинский исследовательский центр гематологии», лаборатория физиологии кроветворения Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationФГБУ «Национальный медицинский исследовательский центр гематологии», научно-консультативное отделение химиотерапии миелопролиферативных заболеваний Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationФГБУ «Национальный медицинский исследовательский центр гематологии», научно-консультативное отделение химиотерапии миелопролиферативных заболеваний Министерства здравоохранения Российской ФедерацииRussian Federation201911122019644424–435Copyright © Петинати Н.А., Шипунова И.Н., Бигильдеев А.Е., Сац Н.В., Челышева Е.Ю., Шухов О.А., Петрова А.Н., Туркина А.Г., Дризе Н.И., 20192019Петинати Н.А., Шипунова И.Н., Бигильдеев А.Е., Сац Н.В., Челышева Е.Ю., Шухов О.А., Петрова А.Н., Туркина А.Г., Дризе Н.И.Petinati N.A., Shipunova I.N., Bigildeev A.E., Sats N.V., Chelysheva E.Y., Shukhov O.A., Petrova A.N., Turkina A.G., Drize N.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/163Введение

Введение. У больных хроническим миелолейкозом (ХМЛ) изменены свойства клеток-предшественниц стромального микроокружения — мультипотентные мезенхимальные стромальные клетки (ММСК) и колониеобразующие единицы фибробластов (КОЕф).

Цель — сравнительное изучение клеток-предшественниц стромального микроокружения ММСК и КОЕф, полученных из костного мозга больных ХМЛ в дебюте заболевания, через год после начала лечения и на длительных сроках лечения ингибиторами тирозиновых киназ (ИТК).

Материалы и методы

Материалы и методы. Были проанализированы характеристики ММСК и концентрация КОЕф в костном мозге больных ХМЛ, а также относительный уровень экспрессии генов (REL), связанных с дифференцировкой и участвующих в регуляции кроветворения. Анализ проводили в дебюте заболевания, через год после начала лечения, через 3–8 лет и через 9–16 лет терапии ИТК. В качестве контроля использовали ММСК и КОЕф здоровых доноров.

Результаты

Результаты. Концентрация КОЕф в дебюте заболевания не отличалась от таковой у доноров, однако в колониях из КОЕф был увеличен относительный уровень экспрессии генов, относящихся к дифференцировке. Через год после начала лечения ИТК концентрация КОЕф снижалась в 4 раза, а затем увеличивалась и достигала нормальных значений через 8 лет приема ИТК. Суммарная клеточная продукция ММСК не была изменена в дебюте заболевания, но снижалась через год приема ИТК с последующим восстановлением. В ММСК больных была изменена экспрессия многих генов: экспрессия REL LIF была увеличена в 10, а JAG1 — в 2 раза, экспрессия REL LIF снижалась по мере лечения, но всегда оставалась выше, чем в ММСК доноров, а экспрессия JAG1 нормализовывалась. В ММСК больных, достигших глубокого молекулярного ответа (ГМО) в течение 17 месяцев лечения, экспрессия REL LIF в дебюте заболевания была в три раза ниже, чем у тех, кто не достиг ГМО за 50 месяцев, а JAG1 не отличался от доноров.

Заключение

Заключение. Изменения в стромальных клетках предшественницах связаны не только с влиянием опухолевых клеток, но и с лечением ИТК. Нормальный уровень экспрессии JAG1 и сниженный уровень экспрессии LIF в ММСК больных ХМЛ в дебюте заболевания могут быть предикторами достижения ГМО.

Конфликт интересов

Конфликт интересов: авторы заявляют об отсутствии конфликта интересов.

Финансирование

Финансирование: исследование не имело спонсорской поддержки.

Introduction

Introduction. The properties of progenitor cells in the stromal microenvironment, i.e. multipotent mesenchymal stromal cells (MMSC) and fibroblast colony-forming units (CFU-F), undergo changes in patients with chronic myelogenous leukaemia (CML).

Aim

Aim. To compare the progenitor cells of the stromal microenvironment (MMSCs and CFU-Fs) obtained from the bone marrow of CML patients at the onset of the disease, one year after the start of the treatment and during the long-term treatment with tyrosine kinase inhibitors (TKI).

Materials and methods

Materials and methods. The study involved an analysis of the characteristics of MMSCs, the concentration of CFU-Fs in the bone marrow of CML patients, as well as the relative expression level of genes (REL) associated with differentiation and involved in the regulation of haematopoiesis. The analysis was performed at the onset of the disease, one year after the start of the treatment, as well as 3–8 and 9–16 years after the TKI therapy. MMSCs and CFU-Fs of healthy donors were used for control purposes.

Results

Results. The concentration of CFU-Fs at the onset of the disease did not differ from that in donors; however, the relative expression level of genes associated with differentiation was increased in the CFU-F colonies. A year after the start of TKI treatment, the concentration of CFU-Fs decreased by four times. Subsequently, the concentration increased to reach normal values following 8 years of TKI treatment. The total production of MMSCs was not changed at the onset of the disease; however, it decreased after a year of TKI treatment, subsequently returning to normal. The expression of many genes was altered in the MMSCs of patients, i.e. the REL of LIF and JAG1 increased by 10 and 2 times, respectively; in the course of treatment, the REL of LIF in MMSCs decreased, always remaining higher than in those of the donors, whereas the expression of JAG1 returned to normal. At the onset of the disease, the REL of LIF in the MMSCs of patients, who achieved a deep molecular response (DMR) within 17 months of the treatment, was three times lower than in the MMSCs of those patients who did not reach DMR within 50 months, with JAG1 not differing from that of donors.

Conclusion

Conclusion. Changes in stromal progenitor cells are associated with the influence of tumour cells, as well as with TKI therapy. A normal expression level of JAG1 and a decreased expression level of LIF in the MMSCs of CML patients at the onset of the disease may be predictive of DMR achievement.

Conflict of interest

Conflict of interest: the authors declare no conflict of interest.

Financial disclosure

Financial disclosure: the study had no sponsorship.

мультипотентные мезенхимальные стромальные клеткихронический миелолейкозотносительный уровень экспрессии генов (ОУЭ)глубокий молекулярный ответmultipotent mesenchymal stromal cellschronic myelogenous leukaemiarelative gene expression leveldeep molecular responseАвторы благодарят Т.В. Сорокину за предоставление РНК из ММСК первичных больных и Н.М. Капранова за предоставление графического изображения результатов иммунофенотипирования ММСК.The authors would also like to thank T. Sorokin for providing RNA from the MMSCs of patients extracted prior to their treatment, as well as to N. Kapranov for providing a graphic image showing the results of MMSC immunophenotypingReferencesTaichman R.S. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood. 2005; 105: 2631–9.Taichman R.S. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood. 2005; 105: 2631–9.Kumar S., Geiger H. HSC Niche Biology and HSC Expansion ex vivo. Trends Mol. Med. 2017; 23: 799–819.Kumar S., Geiger H. HSC Niche Biology and HSC Expansion Ex Vivo. Trends Mol. Med. 2017; 23: 799–819.Morrison S.J., Scadden D.T. The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505: 327–34.Morrison S.J., Scadden D.T. The bone marrow niche for haematopoietic stem cells. Nature. 2014; 505: 327–34.Chen Q., Yuan Y., Chen T. Morphology, differentiation and adhesion molecule expression changes of bone marrow mesenchymal stem cells from acute myeloid leukemia patients. Mol. Med. Rep. 2014; 9: 293–8.Chen Q., Yuan Y., Chen T. Morphology, differentiation and adhesion molecule expression changes of bone marrow mesenchymal stem cells from acute myeloid leukemia patients. Mol. Med. Rep. 2014; 9: 293–8.Shipounova I.N., Petrova T.V., Svinareva D.A. et al. Alterations in hematopoietic microenvironment in patients with aplastic anemia. Clin. Transl. Sci. 2009; 2: 67–74.Shipounova I.N., Petrova T.V., Svinareva D.A. et al. Alterations in hematopoietic microenvironment in patients with aplastic anemia. Clin. Transl. Sci. 2009; 2: 67–74.Shipounova I.N., Petinati N.A., Bigildeev A.E. et al. Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation. Leuk. Lymphoma. 2017; 58: 408–17.Shipounova I.N., Petinati N.A., Bigildeev A.E. et al. Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation. Leuk. Lymphoma. 2017; 58: 408–17.Zhao Z.-G., Liang Y., Li K. et al. Phenotypic and functional comparison of mesenchymal stem cells derived from the bone marrow of normal adults and patients with hematologic malignant diseases. Stem. Cells Dev. 2007; 16: 637–48.Zhao Z.-G., Liang Y., Li K. et al. Phenotypic and functional comparison of mesenchymal stem cells derived from the bone marrow of normal adults and patients with hematologic malignant diseases. Stem. Cells Dev. 2007; 16: 637–48.Estrada-González P.K., Gómez-Ceja L., Montesinos J.J. et al. Decreased frequency, but normal functional integrity of mesenchymal stromal cells derived from untreated and Imatinib-treated chronic myeloid leukemia patients. Leuk. Res. 2014; 38: 594–600.Estrada-González P.K., Gómez-Ceja L., Montesinos J.J. et al. Decreased frequency, but normal functional integrity of mesenchymal stromal cells derived from untreated and Imatinib-treated chronic myeloid leukemia patients. Leuk. Res. 2014; 38: 594–600.Aggoune D., Sorel N., Bonnet M-L. et al. Bone marrow mesenchymal stromal cell (MSC) gene profiling in chronic myeloid leukemia (CML) patients at diagnosis and in deep molecular response induced by tyrosine kinase inhibitors (TKIs). Leuk. Res. 2017; 60: 94–102.Aggoune D., Sorel N., Bonnet M-L. et al. Bone marrow mesenchymal stromal cell (MSC) gene profi ling in chronic myeloid leukemia (CML) patients at diagnosis and in deep molecular response induced by tyrosine kinase inhibitors (TKIs). Leuk. Res. 2017; 60: 94–102.Arrigoni E., Del Re M., Galimberti S. et al. Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment. Stem. Cells Transl. Med. 2018; 7: 305–14.Arrigoni E., Del Re M., Galimberti S. et al. Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment. Stem. Cells Transl. Med. 2018; 7: 305–14.Guzman M.L., Swiderski C.F., Howard D.S., et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl. Acad. Sci. U S A. 2002; 99 (25): 16220–5.Guzman M.L., Swiderski C.F., Howard D.S., et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl. Acad. Sci. U S A. 2002; 99 (25): 16220–5.Horne G., Jackson L., Helgason V., Holyoake T. Stem Cell Guardians — Old and New Perspectives in LSC Biology. Curr. Drug Targets. 2017; 18: 405–13.Horne G., Jackson L., Helgason V., Holyoake T. Stem Cell Guardians — Old and New Perspectives in LSC Biology. Curr. Drug Targets. 2017; 18: 405–13.Rea D., Mahon F-X. How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy. Br. J. Haematol. 2018; 180: 24–32.Rea D., Mahon F-X. How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy. Br. J. Haematol. 2018; 180: 24–32.Bhatia R. Novel approaches to therapy in CML. Hematol Am Soc Hematol Educ Progr. 2017; 2017: 115–20.Bhatia R. Novel approaches to therapy in CML. Hematol Am Soc Hematol Educ Progr. 2017; 2017: 115–20.Bhatia R., McGlave P.B., Dewald G.W. et al. Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. Blood. 1995; 85: 3636–45.Bhatia R., McGlave P.B., Dewald G.W. et al. Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. Blood. 1995; 85: 3636–45.Camacho V., McClearn V., Patel S., Welner R.S. Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment. Int. J. Hematol. 2017; 105: 566–77.Camacho V., McClearn V., Patel S., Welner R.S. Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment. Int. J. Hematol. 2017; 105: 566–77.Sands W.A., Copland M., Wheadon H. Targeting self-renewal pathways in myeloid malignancies. Cell Commun. Signal. 2013; 11: 33.Sands W.A., Copland M., Wheadon H. Targeting self-renewal pathways in myeloid malignancies. Cell Commun. Signal. 2013; 11: 33.Dominici M., Le Blanc K., Mueller I. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8: 315–7.Dominici M., Le Blanc K., Mueller I. et al. Minimal criteria for defi ning multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8: 315–7.Fong T.A., Mosmann T.R. Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines. J. Immunol. 1990; 144: 1744–52.Fong T.A., Mosmann T.R. Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines. J. Immunol. 1990; 144: 1744–52.Свинарева Д.А., Шипунова И.Н., Ольшанская И.В. и др. Основные свойства мезенхимальных стромальных клеток донорского костного мозга: поверхностные маркеры. Терапевтический архив. 2010; 82: 52–6.Svinareva D.A., Shipunova I.N., Ol’shanskaia I.V. et al. The basic properties of mesenchymal stromal cells from the donor bone marrow: superfi cial markers. Terapeuticheskiy arkhiv. 2010; 82: 52–6 (In Russian).Chomczynski P., Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat. Protoc. 2006; 1 (2): 581–5. DOI: 10.1038/nprot.2006.83Chomczynski P., Sacchi N. The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat. Protoc. 2006; 1 (2): 581–5. DOI: 10.1038/nprot.2006.83Schmittgen T.D., Livak K.J. Analyzing real-time PCR data by the comparative CT method. Nat. Protoc. 2008; 3: 1101–8.Schmittgen T.D., Livak K.J. Analyzing real-time PCR data by the comparative CT method. Nat. Protoc. 2008; 3: 1101–8.Frisch B.J., Ashton J.M., Xing L. et al. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2012; 119: 540–50.Frisch B.J., Ashton J.M., Xing L. et al. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2012; 119: 540–50.Lane SW. Bad to the bone. Blood. 2012; 119: 323–5.Lane SW. Bad to the bone. Blood. 2012; 119: 323–5.Sorokina T., Shipounova I., Bigildeev A. et al. The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. Eur. J. Haematol. 2016; 97: 245–52.Sorokina T., Shipounova I., Bigildeev A. et al. The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. Eur. J. Haematol. 2016; 97: 245–52.Maniatis A.K., Amsel S., Mitus W.J., Coleman N. Chromosome pattern of bone marrow fibroblasts in patients with chronic granulocytic leukaemia. Nature. 1969; 222: 1278–9.Maniatis A.K., Amsel S., Mitus W.J., Coleman N. Chromosome pattern of bone marrow fi broblasts in patients with chronic granulocytic leukaemia. Nature. 1969; 222: 1278–9.DiIanni M., Moretti L., Del Papa B. et al. Chronic myeloproliferative disorders: the bone marrow stromal component is not involved in the malignant clone. Leukemia. 2007; 21: 377–8.DiIanni M., Moretti L., Del Papa B. et al. Chronic myeloproliferative disorders: the bone marrow stromal component is not involved in the malignant clone. Leukemia. 2007; 21: 377–8.Estrada-González P.K., Gómez-Ceja L. et al. Decreased frequency, but normal functional integrity of mesenchymal stromal cells derived from untreated and Imatinib-treated chronic myeloid leukemia patients. Leuk. Res. 2014; 38: 594–600.Estrada-González P.K., Gómez-Ceja L. et al. Decreased frequency, but normal functional integrity of mesenchymal stromal cells derived from untreated and Imatinib-treated chronic myeloid leukemia patients. Leuk. Res. 2014; 38: 594–600.Zhang B., Ho Y.W., Huang Q. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012; 21: 577–92.Zhang B., Ho Y.W., Huang Q. et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012; 21: 577–92.Dick J.E. Stem cell concepts renew cancer research. Blood. 2008; 112: 4793–807.Dick J.E. Stem cell concepts renew cancer research. Blood. 2008; 112: 4793–807.Toofan P., Irvine D., Hopcroft L. et al. The role of the bone morphogenetic proteins in leukaemic stem cell persistence. Biochem. Soc. Trans. 2014; 42: 809–15.Toofan P., Irvine D., Hopcroft L. et al. The role of the bone morphogenetic proteins in leukaemic stem cell persistence. Biochem. Soc. Trans. 2014; 42: 809–15.Gerber J.M., Gucwa J.L., Esopi D. et al. Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. Oncotarget. 2013; 4(5): 715–28.Gerber J.M., Gucwa J.L., Esopi D. et al. Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. Oncotarget. 2013; 4(5): 715–28.Laperrousaz B., Jeanpierre S., Sagorny K. et al. Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression. Blood. 2013; 122: 3767–77.Laperrousaz B., Jeanpierre S., Sagorny K. et al. Primitive CML cell expansion relies on abnormal levels of BMPs provided by the niche and on BMPRIb overexpression. Blood. 2013; 122: 3767–77.Zylbersztejn F., Flores-Violante M., Voeltzel T. et al. The BMP pathway: A unique tool to decode the origin and progression of leukemia. Exp. Hematol. 2018; 61: 36–44.Zylbersztejn F., Flores-Violante M., Voeltzel T. et al. The BMP pathway: A unique tool to decode the origin and progression of leukemia. Exp. Hematol. 2018; 61: 36–44.Grockowiak E., Laperrousaz B., Jeanpierre S., et al. Immature CML cells implement a BMP autocrine loop to escape TKI treatment. Blood. 130: 2860–71.Grockowiak E., Laperrousaz B., Jeanpierre S., et al. Immature CML cells implement a BMP autocrine loop to escape TKI treatment. Blood. 130: 2860–71.

The authors declare that there are no conflicts of interest present.