 
  

  

  


  ()          ,                .                     -.             .         ,     .  -, , ,          .           .





 ,  ,  

 



:

      , ,  -             

      ,         . ..   

      , ,   ,          . ..     . . ..   




 


  

    

  

   

    

-           

-    

   

    

  

    

   

   

2     

-?  -

  

   

/    /  

    

4.0       BCR-ABL  4   IS

4.5       BCR-ABL  4,5   IS

5.0       BCR-ABL  5   IS

   

-   , 

    

    

    

    

   

    

   

    

   

   

   

    

    

   

    

   

    

   

BCR-ABL   ,    BCR  ABL

CALR   

CSF3R     -

CTC AE      

DIPSS       

DIPSS+     +  

DRESS      

ELN  European Leukemia Net        

FGFRI     I,  

FISH    in situ

HLA    

IPSS      

IS      BCR-ABL

JAK    

JAK2     II 

JAK-STAT        

JAK2V617F     617 ,          II 

KIT    CD117

KITD816V    D816V   KIT

MIPSS       

MPL    

NCCN  National Cancer Comprehensive Network     

Nordic MPD Study group      

PDGFR?     ,  

PDGFR?     ,  

Ph   

Ph+  ,   

Ph-  ,    

WHO-IPSET           



     . . 







            .               .         ,    ,                 . , ,      ,   ,     .    ,            ,        .    ,               ,   -  .

     ,   ,         ,    ,       .    , ,        .    ,     ,    ,          .                       ,     .            .           -           ,      .

         ,         ,      .     ,            ,      ,    .         , ,  , ,  , ,   .        -      ,   ,     .

  ,                    .







,     ,       .        ,    .                        .                    XIX-   XX- .                     ,  R.Virchow. W.Dameshek                     .            ,          .                BCR::ABL      .       ,       - .                   ,      .                          - .              ,     .  -     ,            JAK-STAT,  - ,    3 (CSF3R),       ,   (PDGFR),  KIT             .          ( ,  - ,   .)    ,              .

         ,      .    ,     ,         .      ,              .




 I.     


  ()    ,             .              .           .

         2016. [1].            :

1. .

2.  .

3. .

4. .

5. .

6.  .

7. , .

 2016.        ,            /   (/) [1, 2].

      ,             [3].       ,         ():

1. .

2. .

3. .

4. .

5.  .

6.  .

7.  .

8. , .

     .       ,           ,     /,         2016. [1].        ()     ()        ()    ()     1019%,         .          (),            .   ,        ()                 (?2%)    (519%)          (      .)           [3].

           - .       ,           ,     .      ,             ,     ,   ,    .  ,              .             .        ,       ,        .       ,       .       ,     CSF3R,             BCR::ABL.               , .

       .  98%         , , , , - [4].           .          0,96  100000   ;   0,95;   () 0,22;  0,51;    () 0,01;   0,03; - 0,41  100000     [4, 5].      . -    :  0,58;  0,83;  1,01;  1,00  100000     [6, 7].           50  : 7,0    (    [8]); 8,5   ; 11,5   ; 20    (       . - [6]),           [9].

                 -  [1].                    ,      ,    ,     [10].

 ,            () ,         ,        .                   ,        [11].    ,     ,      ,       [12].       ,                  [1316].            ,     ,         [12].               ,              -  [1720].

             ,          .

 -          (JAK2)     ,     (MPL),  (CALR),    3-  (CSF3R),       ,   (PDGFR),  KIT (c-KIT),              .          ( ,   .)    ,              ,           [2125].


 

1.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia / D. A. Arber, A. Orazi, R. Hasserjian et al. // Blood. 2016. Vol. 127, 20. P. 23912405.

2.The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes / J. W. Vardiman, J. Thiele, D. A. Arber et al. // Blood. 2009. Vol. 114, 5. P. 937951.

3.The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms / J. D. Khoury, E. Solary, O. Abla et al. // Leukemia. 2022. .

4.Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 20012004, using data from the NAACCR and SEER programs / D. E. Rollison, N. Howlader, M. T. Smith et al. // Blood. 2008. Vol. 112, 1. P. 4552.

5.The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries / V. S. Hoffmann, M. Baccarani, G. Hasford et al. // Leukemia. 2015. Vol. 29, 6. P. 13361343.

6.Ph-Negative Chronic Myeloproliferative Neoplasms  Population Analysis, a Single Center 10-years Experience / V. Shuvaev, I. Martynkevich, A. Abdulkadyrova et al. // Blood. 2014. Vol. 124, 21. P. 5556.

7.     - / . . , . . , . .   . //  . 2011. . 7, 1. . 43.

8.      :           / . . , . . , . .   .//  .     . 2017. . 10, 3. . 390401.

9., . .             . . - . : 14.02.03/ . .  // .:  ǻ  . 2021. 346 .

10.Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms / P. Lundberg, A. Karow, R. Nienhold et al. // Blood. 2014. Vol. 123, 14. P. 2220.

11.International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CMLCP) Treated with Imatinib / M. Deininger, S.G O'Brien, F. Guilhot et al. // ASH Annual Meeting Abstracts. 2009. Vol. 114, 22. P. 1126.

12.          / . . , . . , . . , . .  // . 2014. 3. . 1624.

13.Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center / T. Lahaye, Riehm, B. B., P. Ute et al. // Cancer. 2005. Vol. 103, 8. P. 16591669.

14.               / . . , , . ., , . . . //  .     . 2016. . 9, 3. . 368.

15. :     / . . , . . , . .   . //  .     . 2016. . 9, 1. . 5460.

16.Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia / B. J. Druker, F. Guilhot, S. G. O'Brien et al. // New England Journal of Medicine. 2006. Vol. 355, 23. P. 24082417.

17.Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia: The EURO-SKI study / F.-X. Mahon, J. Richter, J. Guilhot et al. // Blood. 2015. 56th Annual Meeting and Exposition, San Francisco, CA December 69, 2014. P. Abstract 151.

18.Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial / F.-X. Mahon, D. Rea, J. Guilhot, F. Guilhot et al. // The Lancet Oncology. 2010. Vol. 11, 11. P. 10291035.

19.Mahon, F.-X. Discontinuation of tyrosine kinase therapy in CML / F.-X. Mahon // Annals of Hematology. 2015. Vol. 94, 2. P. 187193.

20.Hughes, T. P., Ross, D. M. Moving treatment-free remission into mainstream clinical practice in CML / T. P. Hughes, D. M. Ross // Blood. 2016. Vol. 128, 1. P. 17.

21.Vannucchi, A. M., Guglielmelli, P. Molecular pathophysiology of Philadelphia-negative myeloproliferative disorders: beyond JAK2 and MPL mutations / A. M. Vannucchi, P. Guglielmelli // Haematologica. 2008. Vol. 93, 7. P. 972976.

22.A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis / A. M. Vannucchi, H. M. Kantarjian, J.-J. Kiladjian et al. // Haematologica. 2015. Vol. 100, 9. P. 11391145.

23.Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial / S. Verstovsek, J.-J. Kiladjian, R. Mesa et al. // Blood. 2014. Vol. 124, 21. P. 32013201.

24.Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms / T. Klampfl, H. Gisslinger, A. S. Harutyunyan et al. // New England Journal of Medicine. 2013. Vol. 369, 25. P. 23792390.

25.Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2 / J. Nangalia, C. E. Massie, E. J. Baxter et al. // New England Journal of Medicine. 2013. Vol. 369, 25. P. 23912405.




 II.  


  (,   10 C92.1)   ,      ,          ,     ( ) .             [1].

,   .    ,     ( ,   ),            [2].

   ,         .         ,     .     50- .         20%    .    11,5  100000    [1, 2].      0,58   100000  [3].                       44:56,     49  ( 294 ).    (46,3%)     4060 .      40   30,4%,  60   23,3%.    40      .  40      [4].

       ,   10    ,         3,40  2005.  6,41    100000   2015. [5].               6995   2016. [4].

   .  1960. .  () P. Nowell  D. Hungerford           22,    [6].                 BCR::ABL       9  22 .           ,   ,   1000     ,     [7].












 II-1.    BCR::ABL [7].



  BCR::ABL         .    ,           ,     ,    [810].


 

        -             ,       .   ,                    ,     .               , ,   ,            (      ).            .                 (400500 ? 10


/).          ,    .              ,     ,   .                (- ).          ,         .         ,     ().

        , -         .             (,  , ),   ,               .

        .               .           - .

                      .              .     ,    ,    .         ,    .          Ph-.  45%   Ph-    (    )         9  22 ,    -.           FISH    -    BCR  ABL.    ()   Ph-    810%            ,          .  -        BCR::ABL.      16    BCR::ABL.  95%       BCR      major breakpoint cluster region (M-bcr): b3a2  b2a2    210  (p210);         1  BCR  minor breakpoint cluster region (m-bcr) 12 (p190);  19  BCR  micro breakpoint cluster region (?-bcr) e19a2 (230).    BCR::ABL     BCR  6-  8-  (variable breakpoint cluster region ?-bcr): e6a2 (p185), e8a2 (p200).   BCR::ABL        ABL   3 e13a3 (b2a3, p174), e14a3 (b3a3) [11].

           Ph+    .  Ph+       BCR::ABL    190 ,        BCR::ABL   .         Ph+    FISH  -    BCR  ABL    .                   FISH       BCR  ABL.  Ph+                 ,   FISH   BCR  ABL     (   ) [12, 13].

                    .            (European Leukemia Net  ELN),   2008 [14], 2013 [15]  2020.       ,         (. . .   . . . ) [16]         (National Cancer Comprehensive Network  NCCN) [17].           ()             [18, 19].

.     3 ,    :   (),   (),       ().         .

  ()         ( 80%)   .           .

                    ()    ().

          ,     (, ,  ),  ,      ,    ,      .           .          .           .   ,       .          ,  -   3050%      BCR::ABL,       [1, 5, 15, 20, 21].

  ()   810%               .

  ()     .             12%  .

          .               612  [1, 22]. -  ,      ()     ,   .

     ,     , , ,   .

       ,         ELN [19].         2016.  ,       ,    ,    .       ELN [15]   [23]   . II-1.



 II-1.     ELN [15]   [23]






                     .     ,           ,   .  ,           ,          [24].

.       -     Ph- /   BCR::ABL [21, 33, 34].

              (        )        BCR::ABL: Ph-     (),   (),   ().

 ELN 2020        :

       ;

      ;

      ;         ;

  ()   ;

FISH     BCR  ABL    Ph-;

 -        BCR::ABL;

;

        B.

    (     ),  , ,  1,       , , , ,  ,  , , ,  , ,  ,  (, , , , ), , .          ,       .              .

       BCR::ABL            .               BCR::ABL        [2527].  ,    BCR::ABL   ,     ,           .

    ,     .           ,   .       : , ,   .

 ,      J. E. Sokal, EUTOS  ELTS    II-2.   ELN 2020. [16]       J. E. Sokal [28]  ELTS [29].         J. E. Sokal et al.    1984.         .  ,              ,  , .   ,                         .

 ELTS, ,            ,               ,    .   ,  ,        ,    Sokal.  ,           .  EUTOS                    18  .                          ,            .



 II-2.      J. E. Sokal [28], EUTOS [30]  ELTS [29]








*     : http://bloodref.com/myeloid/cml/sokal-hasford  http://www.leukemia-net.org/content/leukemias/cml/elts_score/index_eng.html

2,72   (0,0116 x (  43,4) + 0,0345 x ( ,  -    7,51) + 0,188 x [((  ? 10


/)/700)


0,563] + 0,0887 x (%   2,10))

0,0025 ? ( / 10)


 + 0,0615 ? ( ,  -  ) + 0,1052 ? (% ) + 0,4104 ? (  ? 10


/)/1000






 ELN 2020                  ()    Ph+ .   ,  : +8,  Ph- (+Ph), i (17q), +19, 7 / 7q-, 11q23, 3q26.2,  .

              .

   ELN 2020              ,    2    .

        6560 (93,8%)       (),  380 (5,5%)  ,  47 (0,7%)  .     Sokal  6560     49:30:21%   ,     .        Sokal ( 30%)     60 .

     307          :   282 (92%) ,   22 (7%) ,   3 (1%) .     . II-3.



 II-3.         




       :

 Sokal  68% /  6% /  26%;

 EUTOS  85% /  15%;

 ELTS  57% /  30% /  13% [31].

.        Ph-      ,          ,    .     ()     ()              [19, 30, 3234].  ,    ELN 2020,      (),  ,     ,         (),                  .    ,  4,0  ,   .

             ,     ,             .

  / -          ().          .                [19, 33].


    

           ,                .                 .      -   BCR::ABL,    BCR::ABL  ,     .            .

                   .     ,                     .     /    (-)             ,      ,          [16, 33].

               : , ,   .        ,        .       II-4.

          BCR::ABL ,    C-KIT, PDGFR- .     ,  , ,     400       600         [35].            (, )   ( 50  400).



 II-4.   




             2    .       .              .           ,                        .      IRIS     10-   ()  83,3%  ,      ()  82,8% [36].       : 10-  82%   German CML study IV [37]               : 10-       . -  67,5% [5],              12-   78,8% [38].       : , ,   :  ,    ,   , , .        :  , , ,    ,   ,         [35].

    BCR::ABL-.           BCR::ABL-     [39, 40].      BCR::ABL  (   Y253H, E255K/V, F359V, T315I) [41].            600/,      800/.         800/     [42].       2          12   3 .     ,        ( 80%),        .         .  ,          ,   , , ,      , ,  , , .           -  ( ,    ).

   ,       .    BCR::ABL    Src (SRC, LCK, YES, FYN), C-KIT, EPHA2, PDGFR?, PDGFR?).       BCR::ABL    T315I, T315A, V299L, F317L/V/I/C [41].  in vitro       BCR::ABL,    ,    SRC (LYN, HCK) [51].        [43].       100/,      140/.             80 1   ,       100 ? 1   ,      80 /.         140 1      .           ,           ,      .  ,          ,        [44].

     ,   BCR::ABL   Src (SRC, LCK, YES, FYN), C-KIT, EPHA2, PDGFR?, PDGFR?.        BCR::ABL T315I, V299L, G250E, E255K/V.           ,                .      500/,        .       600 1 /  ,         8          12  ,        (>3 )  .          400 1   ,      300 /.          (  3050/)     400/.           (   30/)     300/.       ,         200/.  ,      200 1 /        ,  [45].          (, )        ,          810%  [46].

 (, Iclusig [47])       .         ( T315I) BCR::ABL ,    RET, FLT3, KIT,  FGFR, PDGFR  VEGFR.        ,         ,        ,         ,    T315I.            45  .         ,    -,      (         30  15  ,             15      [48]).

  PACE,       FDA,         449     ()    (-, 267 ),   (-, 83 )     (-, 62 )            (Ph+, 32 ),         () (  )     T315I [49].

   55%              BCR::ABL.      267      60%  , 40%   24% 4.5.     73%,        3,4% .   -,         ,   ,    .   -,   , ,    , , 75% (12  16 ), 68% (66  97 ), 44% (63  142 )  58% (7  12 )      .   -,          , 49% (66  136 )  .

         :  (7,3%),  (5,8%),    (4,7%),   (4,5%),    (4,5%),   (4,0%),    (3,8%),  (3,8%),  (3,3%),    (3,1%),   (2,9%),   (2,9%),    (2,7%),    (2,4%),    (2,4%),  (2,4%),  (2,2%),    (2,0%),    (2,0%)     (2,0%).    ,             10%, 7%  9% , .         5% .  ,     25% ,      2 ,         20% .         ,    ,    ,  ,    .

    ,        [5053].     2     ,    ,        2.   ENESTnd           6771%     44%     [54, 55].               2  : 64% ,     46%     [56, 57].

 2           ,      .      172              59% ,      44%  [58].        186               59% ,    49%      [59, 60].           25%  [6163].        :   288       53%   ,       26%  [64].   BFORE    ,    12      47.2%      36,9%   ,     77,2%      66,4% ,   [53].


     

 ,          .            ,          ,      BCR::ABL.

       ,       :

 : ,   ,         [65, 66];

 :  - ,   ,  , -    [6769];

 :       [45].

  [47]:  ,      ;     ;  ;   ;     (HBV);      ;        CYP3A      CYP3A;    ,   ,       ;   ,    - .

           QT,       ,   , .


   BCR::ABL

     BCR::ABL           .                  BCR::ABL      [15, 19].     BCR::ABL         . II-5 [41].



 II-5.  BCR::ABL    










         .           BCR::ABL  (. II-6).



 II-6.       BCR::ABL [16]






*        BCR::ABL ,    in vivo  E255K     E255V       [16].



       (, , , )     T315I.           ,  HLA-    -.    ,                 T315I,   (, Iclusig),   PACE        T315I     72%,   70%,   58%, 4  45%, 4,5  38%,           T315I [70].       ,    ,  , .          T315I    -        [71].  ,    T315I    ,    ,        -.            .


      

        ,   -  ( II-7) [15, 19, 33].           ,    , .



 II-7.     ,   [15, 19, 33]




  ELN2020     ,     BCR::ABL   FISH [16]. ,        .      (,  Ph+)     ( Ph-) ,     .

        ,      ( II-8).            [15, 19, 33].



 II-8.       [15, 19, 33]




1 ,     () ,          FISH (   200 )    ,       1%.




          (IS).        BCR::ABL    1 log      .



                  ELN2020   . II-9 [16].



 II-9.                [16]




*     



                   . II-10 [15, 19].             . II-11 [17].



 II-10.                         [15, 19]



















1     ,  2         800 /,   140 /.




        2,    .      .     (   Sokal,   Ph+ )   .                 .




          12    .




   ,      BCR::ABL ? 1%.



 II-11.                  BCR::ABL (IS)    [17]




                 ,      ,  ,     BCR::ABL.         2.     600800/           2.

           ,    , .   ELN2020        . ,   BCR::ABL>1%       (Ph>0%)      [16].

    ,               -   ,      ,          .

       (  )    (. II-12).     ,     .              .     -.



 II-12.            [15, 19]




             (-)            ,   T315I.         -              /     [15, 19].       HLA-,     -    II-13.



 II-13.   HLA-,         /      [15, 16, 19]




1   ,           -.




   -  EBMT [72]:

   0 ,   1 ,   2 ;

   20  0 , 2040  1 ,  40  2 ;

      -  1  0 ,  1  1 ;

 HLA-  0 ,   1 ;

  - - 1 , 0     -.



          .                       .

                ,     .


        

           .            [73].


 

        .              .         ,     (    , ,  12,    .).           .

    12              .      /  34              .         1,0 ? 10


/,   50 ? 10


/    :

       2 ,      ,    2         (. . 4   );

      ,      1      ;

          (-):    5// ,      -      ;

        (,    )     ,    .

           34         4      .   34 ,      .      ,    34 ,           [73].  ,                            .     1  ,            :

     5%        ;        1   ;         0,510


/    5010


/;         ;   /               -;

    5%             :

      2;

  2  ;

    (,  ).


 

          ,             ,     .        , , ,     ,  , , ,  ,     .              .               ()       ,      .

              . II-14.          /    2      34 .        ( 23 .)    2 .     ,       34 .         ,        ,    .



 II-14.       




               ,          ().           ()                 .      BCR::ABL   ,  4,0  ,   .

                          [7477].    ,         [78],        (3967%)               .

            ELN2020  [16].

 :

  ;

    ;

        (IS)    ;

        ,     6 ,  2    612 ,   3 .

  :

  ,         ;

  BCR::ABL e13a2  e14a2;

   >5  (>4   2);

    (4.0  ) >2 .

 :

   >5 ;

    >3 ,  4.0;

    >2 ,  4.5.



          NCCN   . II-15 [17].



 II-15.       ( NCCN) [17]




  :      .

  :           (,     .

  :    ,   .



         BCR::ABL:

     6 ;

  2    612 ;

   3 .

        ,   2030%     . ,             .          .

    ,              ,       .


  

      ,     .  ,  ,   .

,  ,        ;    2      ;    ;             ;       .

  ELN2020  ,       [16].       , ,     ,         .

            .        .      ,           .

  ,  ,  ,        .   ,   ,             . ,  ,      ,    ,           .

 ,              -       .

            ( ) /    .    -       .     .

  -         ,   .

                   .

         :

     3 ;

     6 ;

     12 .

          :

  3      (BCR::ABL ? 10%)  /     (Ph+ <65%, );

  6      BCR::ABL ? 10%  /     (Ph+ ?35%, );

  1   BCR::ABL ? 1%  /     (Ph+ 0%, );

         ( 3       (BCR::ABL ? 0,1%).

         .             ,              .  ,  ,      .

         II-2.








 II-2.               (  ).



   (  3 )     (4,0  )          ().

          BCR::ABL        :   6  1   ;      ( 7-   12 ) 1   1,5 ;  1   3 .

    BCR::ABL/ABL  0,1%       BCR::ABL     3       ,  1   6    .           .

     307    .   ( )   216 , 91      .       II-16.

           .        :     79 (87%)       9 (10%)   3 (3%) .             ,   .



 II-16.         




*      +, **   +  



            :   2,0      0,5    .

       76  (  54,   19,   2,   1);   46  (  26,   19,   1).

              :   49,5      8,0   .

          32  (  6,   25,   1);    19  (  1,   10,   5,   3).               :   81,3      26,4     .

        27    .

   :    16 ,      11 ,   .       II-17.



 II-17.         




*   



                :   3    64%       74%    ,    12    40%      48%   ,   18      16%    36%   (. II-18).          (p=0,0002).



 II-18.           








               ,     (p=0,0001): 5-      89%,     75% ( II-3).








 II-3.             (n=208)    (n=91).



          46 (51%)     76 (37%)     (p=0,02).      :          13 (14%),     12 (6%), (=0,009);        29 (32%)     59 (28%) (p=0,50);          4 (9%)     5 (2%)  (p=0,54).

          II-18.

  ,                    3      ,              , ,      .

   ,           ,        12              ,     .               .

               ,     ,         , ,              (3,7 )      (10,6 ).



 II-18.           




     (p=0,0005)         : 5-    88%  63% ( II-4).








 II-4.   ,         (n=76)     (n=46).



           19 (41%)     32 (42%)  (p=0,99).   ,      ,    :

     9 (20%)     12 (16%), (=0,77);

     9 (20%)     16 (21%)  (p=0,97);

      1 (2%)     3 (4%)  (p=0,66).

    ,     ,    II-19.



 II-19.           




  ,            ,         12            ,    .             .           ,   ,      ,         .          (3,7 )      (10,6 ), ,    .

      ,   ,       6 (32%)      7 (22%)  (p=0,66).   ,           :

      2 (11%)     3 (9%), =0,62;

      4 (21%)      4 (13%), p=0,33.

    (p=0,0001)         : 3-      100%  64%     ( II-5).

        ,    :

    90 (43%)    ,     (29 )     ,          (58 )  3     -;

    7 (8%) , 4      ,  3      ;

      (p=0,00007)    (0,0041 / )      (0,0024 / ).






 II-5.   ,         (n=32)     (n=19).



        .         BCR::ABL,     3  ,  36%          38%      .

   BCR::ABL,   ,      2,5  ,        6   .

           II-19.



 II-19.          




*   



               (p=0,59) ( II-6).








 II-6.               (n=16)       (n=11).



                     ,    .                 ,          ,           .

                     .          :

        ;

            () 4,0 ( BCR-ABL  0,01%)      .

            2                              2.      -  - [79]                   .         (QALY)      1 QALY     [80].

          ,      [4].      (    ,  , )           ,               [8082].

              3,46  () ,           6,01 ,             5,24 .                 27,8 ,      24,11 .              1 ,       3,7 .

                400 QALY.   1 QALY       724000 ,                1 QALY  621000 .

 ,           ,        .

  ,             .  ,            .

        2,         ,     2                (),              ,        .                2    .                       .                   ,   .

  ,        ,     ,      ,      .         ,    -  ,    ,         ,        [83].


 

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 III.  Ph-        


  Ph-          ,          W. Dameshek   ,     ( ,  ,  ,  ),           [1].        BCR::ABL         ,    (, , )   Ph- .           JAK-STAT   [2, 3].

  Ph-     .      ,         ,          [2426].              ().          5,7 [27]       46/1   JAK2 [28].

      ,                  .     ,      ,    ,        (),     ,       .                    ,     ,  .               .         JAK-STAT  ,         JAK2  617 ,        JAK2V617F [47],     (CALR) [8, 9],   (MPL) [10, 11]     12  JAK2 [30, 31],     JAK-STAT  ,       -    LNK  SH2B3,   208  234 [12],         SOC,   SOC3 [13]   CpG    SOC1  SOC3 [14].         : EZH2 [15]  TET2 [16],   .

               JAK-STAT   :   (),   ()    ().        :

         ;

     JAK2V617F        ;

      ;

  ,      JAK2;

      ,     . [17, 18].

Janus-     .    1849  G?T,         14   JAK2      617.    1100     120140.       ,   :  (JH1),  (JH2),    Sarc  (SH2), FERM .       (JH1)                .   (JH2)     ,          [19].           ,    ,   . SH2       JAK,  FERM,              ,   JAK- [20, 21].




 III-1.   JAK2    ,    [20].



    Janus-    .    Janus-   : JAK1, JAK2, JAK3  TYK2.    JAK2V617F      ,      .           ,     [22].  ,              III-1.



 III-1.         Janus- [23]




   Janus-              .   Janus-     .                JAK-STAT  ,     III-2.         ,   - /   JAK-. Janus-,   ,     . STAT-      ,  ,  Janus-.  STAT-  ,     , ,   ,    [24].            JAK2-  -        [2].            1849   JAK2      ,           617   JH2-  JAK2.              .      JAK-STAT       .




 III-2.  JAK-STAT   [23].



 JAK2V617F         -  ,      JAK-STAT         I : ,     .     ,    JAK2V617F          ,           JAK2 [45].

   JAK2V617F-      (),   ()    ()  ,     JAK2V617F   30%        24%   [25].     JAK2V617F      67,8%    57,6%   [26].     JAK2V617F           () ,       (2615%),      (4826%),  (7224%),  (-)   (-) (4630%)    [27].          :     : ,         JAK2V617F ,  ,    JAK-STAT  .

   EZH2 (    )  TET2 (TET     5-  5-),   JAK2    3%  16%  ,       [15, 28].     (ASXL1, CBL, IDH1/2, IKZF1  .)          ( III-3).    ()              JAK2 .




 III-3. -    [29].



        ,         . ,    ,        (TGF-?),  ,   (PDGFR)      (VEGF),       ,    [30].   ,          ,   ,    CD34+             ,       [3133].           .

                 III-4.




 III-4.              [34].



Lundberg  . 2014.    ,     (. III-5) [35].               JAK2  CALR.         ,    CALR          .




 III-5    -   [35].

1       (, ); 2     (); 3  - ; 4        ; 5        ; 6   



,     CALR


         .      (TET2, DNMT3A, EZH2, ASXL1  .)       ,   ,   .       JAK2  CALR    ,    ,      (  2,  ,     ).       JAK2, DNMT3A, EZH2, ASXL1  .         .     ,   ,    (,  TP53),     de novo   .         ,         (EZH2, ASXL1, IDH1/2, CBL, TP53).            . ,                   (,  53).

 ,          ,       .       ( III-6).




 III-6.         [34].



               .           ,        - ,      .       .          ,   -  , ,     ,     .      -     ,     .       Ph-         ,                       .


 

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