Mafž¼Ì°ø»Ò¤È¼À´µ¡¢È¯´â--¹ü¿ñ¼ð¤Îȯ´â°ø»Ò Multiple myeloma - up date,
Multiple myeloma--Clinical diagnsosis and Pathology

 
 

¿ȯÀ­¹ü¿ñ¼ð¡§molecular pathogenesis, up dates

 

¿ȯÀ­¹ü¿ñ¼ð

Postgerminal center B-cell ͳÍè¤Ç·Á¼ÁºÙ˦¤Ø,¥³¥ß¥Ã¥È¥á¥ó¥È¤µ¤ì¤¿plasmablast¤ò¼ðá絯¸»¤ÎºÙ˦¤È¤·Ê£¿ô¤Î°äÅÁ»Ò°Û¾ï¤¬ÃßÀÑ, ¿Ãʳ¬À­¤Ëȯ¾É¿ÊŸ¤¹¤ë, ʬ²½½ªËöBºÙ˦À­¼ðáç¡£

¿ȯÀ­¹ü¿ñ¼ð¤Ïñ°ì¤Î¼À´µ¤È¤ß¤Ê¤µ¤ì¤Æ¤¤¤ë¤¬, ¼ÂºÝ¤Ï,ºÙ˦ʬ»Ò³ØÅª¤Ë°Û¤Ê¤Ã¤¿Ê£¿ô¤ÎÌÀ³Î¤Ê·Á¼ÁºÙ˦°­À­¼ðáç¤Î½¸¹ç¤Ç¤¢¤ë.*1

 
 

¹ü¿ñ¼ðȯ¾É¤Îʬ»ÒºÙ˦°äÅÁ³Ø

¢£ Biological genetic classification (À¸Êª³ØÅª°äÅÁʬÎà)

¹ü¿ñ¼ðºÙ˦¤Ç¤Ï, Áý¿£¥µ¥¤¥¯¥ë¤Ë¤¢¤ëºÙ˦¤Ï¼ðáçºÙ˦Á´ÂΤÎ1-3%¤Ç¤¢¤ê*2,ºÙ˦ʬÎöÁü¤¬ÆÀ¤é¤ì¤Ë¤¯¤¤¤¿¤á, G-bandË¡¤Ç°Û¾ï¤ò¸¡½Ð¤Ç¤­¤ëÉÑÅ٤Ϲ⤯¤Ê¤¤¡£

¿ȯ¹ü¿ñ¼ð¤ÎÀ÷¿§Âΰ۾︡½ÐÉÑÅÙ¤Ï30-40%¤Ë¤¹¤®¤Ê¤¤ *3¡£¤½¤Î¤¿¤ádel(13)¤äIgHžºÂ¤Ê¤ÉÆÃ°ÛŪ¤ÊÀ÷¿§Âΰ۾︡½Ð¤Ë¤ÏFISH¤¬ÍѤ¤¤é¤ì¤ë¡£*4 *5

 
MM-molecular.jpg

¿ȯÀ­¹ü¿ñ¼ð¤Ï£²¤Ä¤ÎÂ礭¤Ê°äÅÁ¥µ¥Ö¥°¥ë¡¼¥×¤ËʬÎà¤Ç¤­¤ë*6

1. Hyperdiploid myeloma:

À÷¿§Âοô48Ëܰʾå¤Ç, 4N̤Ëþ, chromosome 3, 5, 7, 9, 11, 15, 19, 21¤Î¿ȯ¥È¥ê¥½¥ß-¤ò¤â¤ÁÌȱ֥°¥í¥Ö¥ê¥ó°äÅÁ»Ò¤ÎžºÂ¤ò¤È¤â¤Ê¤ï¤Ê¤¤¤â¤Î.

  • chromosome 3, 5, 7, 9, 11, 15, 19, 21¤Î¥È¥ê¥½¥ß¡¼¤ächromosome 13, 14, 16, 22¤Î¥â¥Î¥½¥ß¡¼¤¬¹âÉÑÅ٤˽и½¤¹¤ë¡£
    ¤³¤ì¤é¤ÏÀ÷¿§Âοô48̤Ëþ¤Înon-hyperdiploid·¿¤È¤½¤ì°Ê¾å¤Ç4N(88)̤Ëþ¤Îhyperdiploid·¿¤ËÂçÊ̤µ¤ìnon-hyperdiploid·¿¤Ïͽ¸å¤¬ÉÔÎɤǤ¢¤ë*7

2. Non-hyperdiploid myeloma:

À÷¿§Âοô48ËṲ̈Ëþ, t(4;14), t(14;16), t(14;20), t(6;14)¤ª¤è¤Ó t(11;14)¤ÇÆÃħŪ¤ÊÀ÷¿§ÂΞºÂ¤ò¤â¤Ä¡£( ÀÄ»ú¤ÎžºÂ¤Ïͽ¸åÉÔÎÉ·² )

Ìȱ֥°¥í¥Ö¥ê¥ó½Åº¿°äÅÁ»Ò(IgH)žºÂ¡Ê14q+)¤ÎÃæ¤Ç¤âÁá´ü¤ÎÉÂÂÖ·ÁÀ®¤Ë´ØÍ¿¤¹¤ë1¼¡À­14q+¤òÍ­¤¹¤ë¡£¼ç¤ËIgH¤Î¥¯¥é¥¹¥¹¥¤¥Ã¥Á¤ÎºÝ¤Î¥¨¥é¡¼¤ÇžºÂ¤¬È¯À¸¤·¶¯ÎÏ¤Ê E¦Á enhancer¤Ë¤è¤ê¹âÉÑÅÙ¤ËæÀ©¸æ¤µ¤ì¹±¾ïŪ¤Ë¹âȯ¸½¤¹¤ë°äÅÁ»Ò¤ËCyclin Ds, FGFR3/MMSET, ÂçMaf(cMaf, MAFA, MAFB)¤¬¤¢¤ë¡£

Ìȱ֥°¥í¥Ö¥ê¥ó°äÅÁ»Ò¤Î´ØÏ¢¤¹¤ëÀ÷¿§ÂΞºÂ¤Ï, MGUS¤Î40-50%, ¿ȯ¹ü¿ñ¼ð¤Î50-70%, ·Á¼ÁºÙ˦À­Çò·ìɤÎ80-85%, human myeloma cell line(¥Ò¥È¿ȯ¹ü¿ñ¼ðºÙ˦³ô)¤Î90%¤Ëǧ¤á¤é¤ì¤ë.

·Úº¿°äÅÁ»Ò¤¬´ØÍ¿¤¹¤ëÉÑÅÙ¤ÏÄ㤤. ¦Ëº¿°äÅÁ»Ò¤ÏMGUS¤Î10%̤Ëþ,¡¡MM¤ä¥Ò¥È¹ü¿ñ¼ðºÙ˦³ô¤Î20%. ¦Êº¿°äÅÁ»Ò¤Ï¤µ¤é¤ËÉÑÅÙ¤¬Ä㤤. *8

 
  • 14q32¾å¤ÎÌȱ֥°¥í¥Ö¥ê¥ó½Åº¿(IgH)°äÅÁ»ÒÎΰè¤Î¶Ñ¹Õ·¿Å¾ºÂ¤¬½ÅÍס£non-hyperdiploid·¿¤Ë¹âÉÑÅ٤˹çÊ»¤¹¤ë¡£
  • žºÂ¥Ñ¡¼¥È¥Ê¡¼¤Ï¼ç¤Ë7¤Ä¤Î°äÅÁ»Ò¤Ç, ¤³¤ì¤é¤Ï3·²¤Ë¤ï¤±¤ë¤³¤È¤¬¤Ç¤­¤ë.
  • CCND·²
    11q13¤ÎBCL1(PRAD/Cyclin D1=CCN D1)°äÅÁ»Ò
     
    12p13¾å¤ÎCCND2°äÅÁ»Ò
     
    6p21¾å¤ÎCCND3°äÅÁ»Ò
  • MAF·²
    8q24.3¾å¤ÎMAFA°äÅÁ»Ò
     
    16q23¾å¤Îc-MAF°äÅÁ»Ò¤Ê¤É¤¬¤¢¤ë
     
    21q12¾å¤ÎMAFB°äÅÁ»Ò
  • FGFR3/ MMSET·²
    4p16.3¾å¤ÎFGFR3/ MMSET°äÅÁ»Ò
     
  • 6p25¾å¤ÎMUM1/IRF4°äÅÁ»Ò
     

t(11;14)(q13;q32)

  • MGUS¤Î15-30%, MM¤Î15-20%¤Ëǧ¤á¤é¤ì¤ë.
  • žºÂ¤Ë¤è¤ê¥µ¥¤¥¯¥ê¥óD(cyclinD, CCND)°äÅÁ»Ò¤Î°ì¤Ä¤Ç¤¢¤ë, CCND1¤¬¹±¾ïŪ¤Ëȯ¸½¤·, ºÙ˦¼þ´ü¿Ê¹Ô¤òÂ¥¿Ê¤¹¤ë¤È¹Í¤¨¤é¤ì¤ë.
  • 14q32/ IGHžºÂ¤Ë¤Ï¤³¤ì¤Þ¤Ç, SHM¤ÈCSR¤¬¤½¤Îµ¡½ø¤È¹Í¤¨¤é¤ì¤Æ¤­¤¿¤¬, ºÇ¶á¤ÎIGHÀÚÃÇÅÀ²òÀϤˤè¤ê, t(11;14)¤Ï̤½ÏBºÙ˦¤¬¹ü¿ñÆâ¤Ç¤ª¤³¤¹DJºÆ¹½À®¤Ç¤âȯÀ¸¤¹¤ë¤³¤È¤¬¼¨¤µ¤ì¤¿.*9
  • ¹ü¿ñÆâ¤Çt(11;14)¤ò³ÍÆÀ¤¹¤ë¤È Mantle cell lymphoma, æõÃæ¿´¤Ç³ÍÆÀ¤¹¤ë¤ÈMM¤òȯ¾É¤¹¤ë¤È¹Í¤¨¤é¤ì¤Æ¤­¤¿¤¬, V(D)JRºÆ¹½À®¤Ë¤è¤êMCL¤À¤±¤Ç¤Ê¤¯MM¤âȯ¾É¤¹¤ë¤È¤¹¤ì¤Ð, É·¿¤Î·èÄê¤Ë¤Ït(11;14)°Ê³°¤ÎÍ×°ø¤¬É¬Íפȿ仡¤µ¤ì¤ë.
  •  

CCN D1, D2, D3°äÅÁ»Ò¤È¹ü¿ñ¼ð

¿ȯ¹ü¿ñ¼ð¤Î, ¤Û¤ÜÁ´¾ÉÎã¤Ëǧ¤á¤é¤ì¤ëÅý°ìŪ¤Ê°Û¾ï¥¤¥Ù¥ó¥È¡£

  • Àµ¾ïBºÙ˦, ·Á¼ÁºÙ˦¤Ç¤ÏcyclinD2¤äcyclinD3¤òȯ¸½¤·¤Æ¤¤¤ë¤¬cyclinD1¤Ï¤Û¤È¤ó¤Éȯ¸½¤·¤Æ¤¤¤Ê¤¤¡£
  • t(11;14)¤ÏMantle lymphoma¤Ç²òÀϤ¬¤¹¤¹¤á¤é¤ì¤Æ¤­¤¿¡£Mantle lymphoma¤Î¾ì¹ç, CCN D1¤ÎDNAÀÚÃÇÅÀ¤ÏCCN D1, ¥»¥ó¥È¥í¥á¥¢Â¦¤Ë¥¯¥é¥¹¥¿¤ò·ÁÀ®¤¹¤ë¡£Â¿È¯¹ü¿ñ¼ð¤Ç¤Ï¤³¤¦¤·¤¿¥¯¥é¥¹¥¿¤Ïǧ¤á¤é¤ì¤ºMantle lymphoma¤È¤ÏžºÂ¥á¥«¥Ë¥º¥à¤¬°Û¤Ê¤Ã¤Æ¤¤¤ë²ÄǽÀ­¤¬¤¢¤ë¡£
MMprogress02.jpg

¹ü¿ñ¼ð¤Ç¤ß¤é¤ì¤ë14qžºÂ¤Ï10¼ïÎà°Ê¾å¤¬Â¸ºß¤·, ¶¯È¯¸½¤¹¤ë°äÅÁ»Ò¤Î¼ïÎà¤Ë¤è¤ê°Ê²¼¤Î1)¡Á4)¤ËÂçÊ̤µ¤ì¤ë.

1). cyclin D ¥°¥ë¡¼¥×

  • cyclin D ¥°¥ë¡¼¥×¤Ë¤Ï t(11;14), t(6;14), t(12;14)¤¬´Þ¤Þ¤ì, ÉÑÅ٤ϳơ¹MM¾ÉÎã¤Î, 15-20%, 2¡Á3%, <1%¤Ç¤¢¤ë.
     
  • 14q¤Ë¶Éºß¤¹¤ëIgH enhancer¤Ë¤è¤ê¤½¤ì¤¾¤ì cyclin D1, cyclin D2, cyclin D3¤¬°Û½êÀ­¤Ë³èÀ­²½¤µ¤ì¤ë.
     
  • t(11;14)¤ÏMantle lymphoma¤Ç²òÀϤ¬¤¹¤¹¤á¤é¤ì¤Æ¤­¤¿¡£Mantle lymphoma¤Î¾ì¹ç, CCN D1¤ÎDNAÀÚÃÇÅÀ¤ÏCCN D1, ¥»¥ó¥È¥í¥á¥¢Â¦¤Ë¥¯¥é¥¹¥¿¤ò·ÁÀ®¤¹¤ë¡£Â¿È¯¹ü¿ñ¼ð¤Ç¤Ï¤³¤¦¤·¤¿¥¯¥é¥¹¥¿¤Ïǧ¤á¤é¤ì¤ºMantle lymphoma¤È¤ÏžºÂ¥á¥«¥Ë¥º¥à¤¬°Û¤Ê¤Ã¤Æ¤¤¤ë²ÄǽÀ­¤¬¤¢¤ë¡£
     
  • MMºÙ˦¤Ç¤ÏÌó20%¤Ët(11;14)(q13;q32)¤¬Ç§¤á¤é¤ìCCND1¤Î¹âȯ¸½¤¬¤¢¤ë¡£
     
  • t(11;14)-positive ¿ȯ¹ü¿ñ¼ð¤Ç¤Ï, žºÂ¤Ë¤è¤êÌȱ֥°¥í¥Ö¥ê¥ó½Åº¿(IgH)¤Î¶¯ÎϤʥ¨¥ó¥Ï¥ó¥µ¡¼¤Ç¤¢¤ëE¦Á¤Ë¤è¤êCCN D1°äÅÁ»Ò¤¬Å¾¼Ì¤µ¤ìÀµ¾ï·Á¼ÁºÙ˦¤Ë¤Ïȯ¸½¤·¤Ê¤¤CCN D1¥¿¥ó¥Ñ¥¯¤Î¹±¾ïŪ¤Ê¹âȯ¸½¤¬¤ß¤é¤ì¤ë¡£
     
  • 14q32/IGHžºÂ¤Îµ¡½ø¤È¤·¤Æ, ¤³¤ì¤Þ¤Çsomatic hypermutation¤äclass switch¤¬¹Í¤¨¤é¤ì¤Æ¤­¤¿.
    ¤·¤«¤·ºÇ¶á, IGHÀÚÃÇÅÀ²òÀϤˤè¤ê t(11;14)¤ÏDJºÆ¹½À®¤Ç¤â¤ª¤³¤ë¤³¤È¤¬¼¨¤µ¤ì¤¿. *10
     
  • DJºÆ¹½À®¤Ï¹ü¿ñ¤Ç̤½ÏBºÙ˦¤¬µ¯¤³¤¹°äÅÁ»ÒºÆ¹½À®¤Ç, ¤³¤ì¤Þ¤Ç¤Ï¹ü¿ñ¤Çt(11;14)¤ò³ÍÆÀ¤¹¤ì¤Ðmantle cell lymphoma(MCL), æõÃæ¿´¤Çt(11;14)¤ò³ÍÆÀ¤¹¤ì¤ÐMM¤òȯ¾É¤¹¤ë¤È¹Í¤¨¤é¤ì¤Æ¤­¤¿¤¬, V(D)JºÆ¹½À®¤Ç¤âMCL¤À¤±¤Ç¤Ê¤¯MM¤âȯ¾É¤¹¤ë¤Ê¤é, É·¿¤Î³ÎÄê¤Ë¤Ï¤³¤ÎžºÂ°Ê³°¤ÎÍ×°ø¤¬É¬Íפȿ仡¤µ¤ì¤ë.
     
  • ¤³¤ÎžºÂ¤ò¤â¤ÄMM¤ÎÆÃħ¤È¤·¤Æ, ¥ê¥ó¥Ñ·Á¼ÁºÙ˦ÍÍ·ÁÂÖ¤ò¤È¤ë, IgM·¿, ÈóʬÈç·¿, CD20+, CD56+ MM¤ÎÉÑÅÙ¤¬¹â¤¤*11¤³¤È¤¬¤¤¤ï¤ì¤Æ¤¤¤ë¤¬, ÈÝÄêŪ¤ÊÊó¹ð¤¬¤¢¤ë.*12
     
  • ¤³¤ÎžºÂ¤ò¤â¤ÄMM¤Îͽ¸å¤Ë´Ø¤·¤Æ¤Ï·ëÏÀ¤Ï¤Ç¤Æ¤¤¤Ê¤¤. *13
     
  • CCN D3¤Ï6p21¤Ë°ÌÃÖ¤·, IgH°äÅÁ»Ò¤ÈžºÂ¤·¤¿¾ì¹ç[t(6;14)(p21;q32)], ¤â¤·¤¯¤Ït(11;14)¤òÍ­¤¹¤ë¾ÉÎã¤Ç¹âȯ¸½¤¹¤ë¤è¤¦¤Ç¤¢¤ë¤¬¡¢¤½¤Îµ¡½ø¤ÏÉÔÌÀ¤Ç¤¢¤ë¡£
     
  • CCN D2¤Ï12q13¤Ë¶Éºß¤¹¤ë°äÅÁ»Ò¡£IgH¤È¤ÎžºÂ¤Ï¤­¤ï¤á¤Æ¤Þ¤ì(<1%)¤Ç¡¢¤½¤Î¹âȯ¸½¤Ï¹ü¿ñ¼ð¤Ë¤ª¤±¤ëMaf(16q23), Maf-B(20q11)¤Ê¤É¤ÎCCN D2¤òɸŪ¤È¤¹¤ëž¼Ì°ø»Ò¤¬Å¾ºÂ¤·¤¿¤³¤È¤Ë¤è¤ë²á¾êȯ¸½¤¬¸¶°ø¤Ç¤¢¤ë¤È¤µ¤ì¤ë¡£¡¡¤Þ¤¿ºÇ¶á¿·¤¿¤Êž¼Ì°ø»ÒZKSCAN3¤ÈCCN D2¹âȯ¸½¤È¤Î´ØÏ¢¤â¹ü¿ñ¼ðºÙ˦¤ÇÊó¹ð¤µ¤ì¤Æ¤¤¤ë¡£
     
  • ²¼µ­, 2)MMSET, 3)Maf¤Î°Û¾ï¤Ç¤ÏCCN D2°äÅÁ»Ò¤¬É¸Åª°äÅÁ»Ò¤È¤Ê¤ê, CyclinD2¤Î¶¯È¯¸½(Áý²Ã)¤¬Ç§¤á¤é¤ì¤ë. (±¦¿Þ)

2). MMSET/FGFR3 ¥°¥ë¡¼¥×

  • t(4;14)¤Ï¹ü¿ñ¼ð¾ÉÎã¤Î15-20%¤òÀê¤á, ÀÚÃÇÅÀ¤Ï¿¤¯¤ÎÎã¤Ç¥Ò¥¹¥È¥ó¥á¥Á¥ë²½¹ÚÁÇ MMSET¤Î¥×¥í¥â¡¼¥¿Îΰè¡Áexon4¤Ë°ÌÃÖ.
    Á´Ä¹·¿¤Ê¤¤¤·, alternative splicing¤Ë¤è¤êû½Ì·¿¤ÎMMSET¤òȯ¸½¤¹¤ë.
MMSET-FGFR3.jpg
  • ¶¯È¯¸½¤·¤¿MMSET¤ÏH3K36(histon3¤Î36ÈÖÌܤΥꥸ¥ó»Ä´ð)¤ÈH3K27¤Î¥á¥Á¥ë²½¤ò¤½¤ì¤¾¤ìÂ¥¿Ê, ÍÞÀ©¤· cyclin D2 °äÅÁ»Ò¤ò´Þ¤àÍÍ¡¹¤Ê°äÅÁ»Ò¤Îȯ¸½¤òͶƳ¤¹¤ë.
     
  • 4p16¤ÏÀ÷¿§ÂÎËöü¤Ë¶á¤¯, žºÂ¤ÎÀ÷¿§Âι½Â¤ÊѲ½¤¬ÈùºÙ(cryptic translocation)¤Ç¤¢¤ê, ³Ë·¿Ê¬ÀϤˤè¤ë¸¡½Ð¤Ïº¤Æñ. FISHʬÀϤ¬É¬Í×.*14
     
  • MGUS¤Î3-10%, MM¤Î15-20%¤Ë¸¡½Ð¤µ¤ì¤ë. MGUS<MM¤ÈÉÑÅ٤˺¹¤¬¤¢¤ë¤³¤È¤ÏMGUS¤Î»þ´ü¤¬Ã»¤¤¤³¤È¤ò¼¨º¶¤·¤Æ¤¤¤ë.*15
     
  • IGHºÆ¹½À®¤Ë¤è¤êIGH¥¨¥ó¥Ï¥ó¥µ¡¼E¦Ì¤¬4ÈÖÀ÷¿§ÂÎ¤Ë°ÜÆ°, MMSET(multiple myeloma set domain)°äÅÁ»Ò¤Îȯ¸½¤Ë´Ø¤ï¤ë*16.
    °äÅÁ»Ò»ºÊª¤ÎMMSET¤Ï¥Ò¥¹¥È¥ó¥á¥Á¥ë²½¹ÚÁǤǥ¨¥Ô¥¸¥§¥Í¥Æ¥£¥Ã¥¯¥¹¤Ë´ØÍ¿¤·¤Æ¤¤¤ë.
     
  • Ê̤Υ¨¥ó¥Ï¥ó¥µ¡¼3'E¦Á¤Ï, 14ÈÖÀ÷¿§ÂΤ˻Ĥê, °Üư¤·¤Æ¤­¤¿FGFR3(fibroblast growth factor receptor3)°äÅÁ»Ò¤Îȯ¸½¤Ë´Ø¤ï¤ë. FGFR3¤Ï¥ì¥»¥×¥¿¡¼·¿¥Á¥í¥·¥ó¥ê¥ó»À²½¹ÚÁÇ.
     
  • ¤³¤ÎžºÂ¤Î25%¤ÏÉԶѹÕžºÂ¤Ç, ÇÉÀ¸14ÈÖÀ÷¿§ÂΤò·ç¼º¤·¤ÆFGFR3¤Îȯ¸½¤ò·ç¤¤¤Æ¤¤¤ë. ¤·¤«¤·MMSET¤ÏÁ´¾ÉÎã¤Çȯ¸½¤·¤Æ¤ª¤ê, MMȯ¾É¤Ë¤ÏMMSET¤¬¤è¤ê¶¯¤¯´ØÍ¿¤·¤Æ¤¤¤ë¤È¹Í¤¨¤é¤ì¤ë.*17*18
     
  • IgA¥¯¥é¥¹¤ÎMM¤¬Â¿¤¯, ·Úº¿¤Ç¤Ï¦Ëº¿¤¬Â¿¤¤. CCND2ȯ¸½¤¬Ð¶¿Ê¤·¤Æ¤¤¤ë¤¬¤½¤Îµ¡½ø¤Ï¤Þ¤ÀÌÀ¤é¤«¤Ç¤Ï¤Ê¤¤. ¤Þ¤¿13ÈÖÀ÷¿§ÂΤη缺¤ò90%°Ê¾å¤Ëǧ¤á¤ë.
     
  • ͽ¸åÉÔÎɤǤ¢¤ë.

3). MAF ¥°¥ë¡¼¥×

  • t(14;16), t(14;20), t(8;14)¤¬´Þ¤Þ¤ì, ¤½¤ì¤¾¤ìMAF family ž¼Ì°ø»Ò¤Î c-Maf, MafB, MafA¤ò¶¯È¯¸½¤·¤Æ·Á¼ÁºÙ˦¤ò¼ðáç²½¤·¤Æ¤¤¤ë¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.
     
  • ɸŪ°äÅÁ»Ò¤È¤·¤Æ¤Ïcyclin D2*17¤äÀÜÃå°ø»Ò¤ÎCCR1, ¦Â7integlin¤Ê¤É¤¬ÃΤé¤ì¤Æ¤¤¤ë.
     
  • 16q23¤ÏÀ÷¿§ÂÎËöü¤Ë¶á¤¯cryptic translocation¤Ë¤Ê¤ë¤¿¤á¸¡½Ð¤Ë¤ÏFISH¤¬É¬ÍפǤ¢¤ë.
     
  • MGUS¤Ç¤Ï¤Þ¤ì¤Ç, MM¤Ç¤Ï2-10%¤Ëǧ¤á¤é¤ì¤ë. MGUS¤ÈMM¤Î´Ö¤ËÉÑÅÙº¹¤¬¤ß¤é¤ìMGUS¤Î´ü´Ö¤¬Ã»¤¤²ÄǽÀ­¤¬¤¢¤ë.
     
  • Ìȱ֥°¥í¥Ö¥ê¥ó¥¯¥é¥¹Ê̤Ç¿¤¤¤Î¤ÏIgA¤È¤¹¤ëÊó¹ð¤ÈIgG¤È¤¹¤ëÊó¹ð¤¬¤¢¤ë.CD56¤òȯ¸½¤·¤Ê¤¤Î㤬¿¤¯13ÈÖÀ÷¿§Âη缺¤ò70%°Ê¾å¤Ëǧ¤á, ͽ¸åÉÔÎɤǤ¢¤ë.*13¡¡*19¡¡*15
     
  • c-MAFÍÛÀ­¹ü¿ñ¼ð¤Ï±¢À­¹ü¿ñ¼ð¤ËÈæ³Ó¤·¤Æ, Çò·ìµåÁý²Ã, ·ì¾®Èĸº¾¯, Áý¿£Â®ÅÙ¤¬Â®¤¤(G-band³Ë·¿ÍÛÀ­Î㤬¿¤¤)·¹¸þ¤¬¤¢¤ë*19 *20¤Û¤«, CD56±¢À­Î㤬¿¤¤.
     
  • c-MAFÍÛÀ­Îã¤Ç¤ÏºÙ˦ÀÜÃå°ø»Ò¤ÎCD56(NCAM)¤¬±¢À­¤Î¤¿¤á, ¹ü¿ñ¼ðºÙ˦Çò·ì²½¤¬ÍưפǤ¢¤ë¤³¤È¤Ë²Ã¤¨¤ÆºÙ˦Áý¿£¤¬Â®¤¤¤¿¤á¤ËÀ¸Ì¿Í½¸å¤¬ÉÔÎɤǤ¢¤ë¤È¿ä»¡¤µ¤ì¤Æ¤¤¤ë*19.

4). ¤½¤Î¾

°Ê¾å ·Á¼ÁºÙ˦¼ðáç²½¤Î½é´ü¤Ë¤Ïcyclin D¤Îȯ¸½Ð¶¿Ê¤¬¶¦Ä̤·¤Æ¤¤¤ë.

  • ¥Þ¥¤¥¯¥í¥¢¥ì¥¤¤Ë¤è¤ëÌÖÍåŪ²òÀϤǤÏ, ¤Û¤ÜÁ´Îã¤Î¹ü¿ñ¼ð¤ÇCCN D1-D3°äÅÁ»Ò¤Î¤¤¤º¤ì¤«¤Î¹âȯ¸½¤ò³Îǧ¤·¼ðáç²½¤ÎÁá´ü¤Ëµ¯¤³¤ëºÇ½é¤Î°äÅÁ»Ò°Û¾ï¤Ç¤¢¤ë¤È·ëÏÀ¤µ¤ì¤Æ¤¤¤ë¡£*21
    3¤Ä¤ÎCCN D°äÅÁ»Ò¤Îȯ¸½¤ÏÀ÷¿§ÂΞºÂ°Ê³°¤Îµ¡½ø¤Ë¤è¤ë²ÄǽÀ­¤¬¤¢¤ë¡£
  • cyclin D¤Ï CDK4/6¤ÈÊ£¹çÂΤò·ÁÀ®¤·RB¥¿¥ó¥Ñ¥¯¤ò¥ê¥ó»À²½, G1´ü¤«¤éS´ü¤Ø¤Î¿Ê¹Ô¤òÂ¥¿Ê¤µ¤»¤ë. ËÜÍèÀµ¾ï¤Ç¤ÏÁý¿£Ç½¤ò¤â¤¿¤Ê¤¤·Á¼ÁºÙ˦¤¬growth advantage¤ò¤â¤ÁMGUS¤Ë·Á¼Áž´¹, ¿ÊŸ¤µ¤»¤ëÌò³ä¤ò¤Ï¤¿¤·¤Æ¤¤¤ë¡£
  • t(11;14)¤ÎÀ÷¿§ÂΞºÂ¤ò¤â¤¿¤ºRNA¥ì¥Ù¥ë¤ä¥¿¥ó¥Ñ¥¯¥ì¥Ù¥ë¤ÇCCN D1¤Îȯ¸½¤ß¤é¤ì¤ë¾ÉÎã¤Ç¤Ï, ¤½¤Îµ¡½ø¤È¤·¤Æ¥Ý¥ê¥½¥ß¡¼11¤Ë¤è¤ë°äÅÁ»Ò¤ÎÎÌŪ¤Ê¸ú²Ì¤¬Êó¹ð¤µ¤ì¤Æ¤¤¤ë¡£--> ¹âÆóÇÜÂΤιà
  • t(4;14)¤Èt(14;16)¤Ïͽ¸åÉÔÎɤȹͤ¨¤é¤ì¤Æ¤¤¤ë¡£

¹âÆóÇÜÂβ½¤Ç¤Ï, ´ñ¿ôÈÖ¹æ¤ÎÀ÷¿§ÂÎ (3, 5, 7, 9, 11, 15, 19, 21ÈÖ )¤Îtrisomy¤¬ÆÃħŪ

  • ¼ðáç²½¤Î¥á¥«¥Ë¥º¥à¤Ï¤Þ¤À½½Ê¬¤Ë¤Ï²òÌÀ¤µ¤ì¤Æ¤¤¤Ê¤¤¤¬, 11ÈÖÀ÷¿§ÂΤǤÏtrisomy¤Ë¤è¤ëcopy¿ôÁý²Ã¤Çcyclin D1ȯ¸½¤¬¾å¾º¤¹¤ë.
 
 

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2.NF-kB, HIF1/2, XBP-1¤Ê¤É¹ü¿ñ´Ä¶­¤ËŬ±þ¤¹¤ë¤¿¤á¤Ë²á¾êȯ¸½¤ò¤·¤Æ¤¤¤ë¤â¤Î¤Ê¤É¤¬¤¢¤ë¡£

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1. t(4;14)žºÂ¤Ë¤è¤ë¿ȯ¹ü¿ñ¼ðSET¥É¥á¥¤¥ó¥¿¥ó¥Ñ¥¯¼Á(MMSET)¹âȯ¸½¤È¥Ò¥¹¥È¥ó¥ê¥¸¥ó¥á¥Á¥ë²½

2. DNA¤ª¤è¤Ónon-cording RNA¤Î¥á¥Á¥ë²½°Û¾ï

3. ¥Ò¥¹¥È¥ó楢¥»¥Á¥ë²½¹ÚÁÇÁ˳²¤Ë¤è¤ë¹³¼ðáç¸ú²Ì

¢£MMSET(Official full name: Wolf-Hirschhorn syndrome candidate 1¡¡[provided by HGNC], Also known as WHS; NSD2; TRX5; MMSET; REIIBP)

  • 4p16.3¤Ë¶Éºß¡£¤³¤Î°äÅÁ»Ò¤Ï PWWP domain, HMG box, SET domain, ¤ª¤è¤Ó PHD-type zinc finger¤Î4¥É¥á¥¤¥ó¤ò¤â¤Ä¥¿¥ó¥Ñ¥¯¼Á¤ò¥³¡¼¥É¤·¤Æ¤¤¤ë¡£Áá´üȯÀ¸¤Ë¤ª¤¤¤Æ¤Ó¤Þ¤óÀ­(¥æ¥Ó¥­¥¿¥¹)¤Ë¸ºß¤¹¤ë¡£ Wolf-Hirschhorn syndrome (WHS)¤ÏÂè4À÷¿§Âαó°ÌûÏӤηç»(hemizygous deletion)¤Ë¤è¤êȯÀ¸¤¹¤ë¡£ËܰäÅÁ»Ò¤ÏWHS¤Î½ÅÍפÊ165kbÉôʬ¤Ë°ÌÃÖ¤·¤Æ¤ª¤ê¿ȯÀ­¹ü¿ñ¼ð¤Ç¤Ît(4;14)(p16.3;q32.3)¤Ë¤è¤Ã¤Æ¤â¾ã³²¤ò¤¦¤±¤ë¡£ °äÅÁ»Ò¤Îalternative splicing¤Ë¤è¤êÊ£¿ô¤Îž¼Ì¥ô¥¡¥ê¥¢¥ó¥È¤òÍ褷°Û¤Ê¤ëisoform¤òÀ¸À®¤¹¤ë¡£ Some transcript variants are nonsense-mediated mRNA (NMD) decay candidates, hence not represented as reference sequences. [provided by RefSeq, Jul 2008]
  • MMSET¤Ë¤ÏÊ£¿ô¤Îž¼Ì»ºÊª¤¬¤¢¤ê, MMSET typeI, typeII, typeIII¤Ê¤É¤Îsplicing variant¤òÍ­¤¹¤ëMMSET¤È¡¢¤½¤Î¥¢¥¤¥½¥Õ¥©¡¼¥à¤Ç¤¢¤ëprotein response element II binding protein(RE-IIBP)¤È¤¬¤¢¤ë¡£ ¤½¤ì¤¾¤ì¤¬t(4;14)¹ü¿ñ¼ð¤ËÆÃ°ÛŪ¹âȯ¸½¤ò¤¹¤ë¡£
  • t(4;14)(p16;q32)¤Ï¹ü¿ñ¼ð¤Î15-20%¤Ë¤ß¤é¤ìMMSET¤È'FGFR3°äÅÁ»Ò¤Î²á¾êȯ¸½¤òÍ褹¤¬¡¢¤³¤ÎžºÂ¤ò¤â¤ÄÎã¤ÎÌó30%¤ÏMMSET¤Î¤ß¤ò²á¾êȯ¸½¤¹¤ë¡£*24

¢£MMSET¤Ë¤è¤ë¥Ò¥¹¥È¥ó¥ê¥¸¥ó¥á¥Á¥ë²½¤Èž¼ÌÀ©¸æ

  • H3K36me2: ž¼Ì³èÀ­²½*25
     
  • H3K36me3: ž¼ÌÍÞÀ©*26
     
  • H4K20me3: ž¼ÌÍÞÀ©*27
     
  • H3K27me2: ž¼ÌÍÞÀ©*28
     
  • H4K20me2, me3: DNA½¤Éü*24

Kuo¤é*25¤ÎÊó¹ð¤Ç¤ÏMMSET¤Î¥Ò¥¹¥È¥ó¥ê¥¸¥ó¥á¥Á¥ë²½³èÀ­¤Ë¤è¤êH3K36¤Î¥¸¥á¥Á¥ë²½¤Î¤ß¤¬Í¶Æ³¤µ¤ìH3K36me2¤Ï¿Ê¹ÔÃæ¤Îž¼ÌÎΰè¤ò¥Þ¡¼¥¯¤¹¤ë¤è¤¦¤ËʬÉÛ¤·¤½¤Î·ë²Ì¤È°ìÃפ·¤Æ´â´ØÏ¢°äÅÁ»Òž¼Ì³èÀ­²½¤¬¤ª¤³¤ë¤³¤È¤¬¼¨¤µ¤ì¤¿¡£ °Ê¾åMMSET¤Î¥Ò¥¹¥È¥ó¥á¥Á¥ë²½È¯¤¬¤ó³èÀ­¤ÏH3K36me2¤Ëµ¯°ø¤·¤Æ¤¤¤ë¤ÈÀâÌÀ¤µ¤ì¤Æ¤¤¤ë¡£

Multiple myeloma¤Îȯ¾É¡¦¿ÊŸ

¿ȯ¹ü¿ñ¼ð¤ÎÆó¼¡Åª°äÅÁ»Ò°Û¾ï

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  • NRAS, KRAS, ¤¢¤ë¤¤¤ÏBRAF¤Î³èÀ­²½ÊѰÛ
     
  • NFkappaB¤Î³èÀ­²½
     
  • Copy number abnormality(CNA)
    • 17p13 deletion
       
    • 1q21 gain
       
    • 13q deletion
       
    • 1p deletion ---1p12¤ÎFAM46C, 1p32¤ÎCDKN2C¤ÇÊѰۤ¬¸¡½Ð¤µ¤ì¤Æ¤¤¤ë.
       

MYC¤ÎºÆ¹½À®¡¦ÁýÉý

  • IgH-MycžºÂ¤Ï, MM½é¿Ç»þ¤Î10%Á°¸å¤Ëǧ¤á¤é¤ì¤ë¤Î¤ËÂФ·, MGUS¤Ç¤Ï3%¤Ë¤È¤É¤Þ¤ê, °ìÈ̤ËÉÂÂÖ¿ÊŸ¤Ë´ØÍ¿¤·¤¿°Û¾ï¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.*29
     
  • MyelomaIX²òÀÏ*30¤Ç¤Ï,¡¡Myc¤ÎžºÂÁê¼ê¤Ï¿´ô¤Ë¤ï¤¿¤ê, IgH(16%), IgL(16%), IgK(6%)¤Î¾, FAM46C(9%),FOXO3(6%), BMP6(3%). Myc¤ÎžºÂ18.4%¤Ç¤¢¤ê, IgH-MYC''¤ÎÉÑÅÙ¤Ï, Ìó3%¤È¤Ê¤ë.
     
  • žºÂ¤Ë¤è¤é¤Ê¤¤, MycÁýÉý¤¬14%¤ß¤é¤ì, Á´ÂΤȤ·¤ÆMyc¤ÎžºÂ¡¦ÁýÉý¤ÏMM¤Î32%¤Ë¸¡½Ð¤µ¤ì¤¿.
     
  • MYC¥¿¥ó¥Ñ¥¯È¯¸½¤Ï, žºÂ¾ÉÎã¤Ç¤ÏÁý²Ã¤·¤Æ¤¤¤¿¤¬, ÁýÉý·²¤Ç¤Ïȯ¸½Ð¶¿Ê¤Ï¤ß¤é¤ì¤Ê¤«¤Ã¤¿.
     
  • MYCžºÂ¾ÉÎã, ÁýÉý¾ÉÎã¤È¤â, MYCÀµ¾ï¾ÉÎã¤è¤ê¤âOS¤ÏÉÔÎɤǤ¢¤Ã¤¿.
     
  • Myc¤ÏMyc¶á˵¤ÎÊѰ۹¥È¯Éô°Ì(Kataegis)¤¬Å¾ºÂ¹¥È¯Éô°Ì¤È¤Ê¤ê, ¤µ¤é¤ËžºÂÀè¶á˵¤Î¥¨¥ó¥Ï¥ó¥µ¡¼¤òÍøÍѤ·¤ÆÈ¯¸½Ð¶¿Ê¤¹¤ë¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.(super enchancer)
     
  • MycžºÂ¤Ï, hyperdiploid·²¤Ç60%¤Ë¤ß¤È¤á¤é¤ì¤ë¤ÎÂФ·¤Æ, t(4:14)¤Ç¤ÏÍ­°Õ¤ËÉÑÅÙ¤¬Ä㤤.

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monosomy13¤ÏG-bandË¡¤Ç10-20%¤Ë¸¡½Ð¤µ¤ì, FISH¤Ë¤è¤ëp53¤Î·ç¼º[ del(17p13)]¤È¤È¤â¤Ëͽ¸åÉÔÎɰø»Ò¤È¤¤¤ï¤ì¤Æ¤¤¤¿¤¬, International myeloma working group(IMWG)¤Ë¤è¤ì¤Ð¸½¾õ¤Ç¤Ï¾¤Î¥Þ¡¼¥«¡¼¤ÈÈæ³Ó¤·¤ÆÍ½¸å¤È¤ÎÁê´Ø¤¬Ä㤤¤È¤µ¤ì¤Æ¤¤¤ë¡£

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±¦¿Þ¡§¹ü¿ñ¼ð¤Î¿Ãʳ¬È¯¤¬¤ó*32 *33

MGUS¤«¤é¹ü¿ñ¼ð¤Ø¤Î¿ÊŸ

ÄêµÁ¤Ï CD19-/ CD45-/low¼ðáçÀ­plasma cell¤¬¹ü¿ñÍ­³ËºÙ˦¤Î10%°Ê¾å¤òÀê¤á¤ë¤è¤¦¤Ë¤Ê¤Ã¤¿¾ì¹ç.

  • MGUS¤«¤é¹ü¿ñ¼ð¤Ø¤Î¿ÊŸ¤Ë¤Ï¤µ¤é¤Ëgrowth advantage¤Î³ÍÆÀ¤¬É¬ÍפÇ, ¤½¤Î¼ç°ø¤ÏRas¤ÎÆÍÁ³ÊѰÛ.
  • K-rasÊѰۤÏMGUS¤Ç¤ÏÁ´¤¯Ç§¤á¤é¤ì¤Ê¤¤¤¬, ¹ü¿ñ¼ð¤Ç¤ÏÌó30%¤Ë´Ñ»¡¤µ¤ì¿ÊŸ¤ÎÆÃ°ÛŪ¥Þ¡¼¥«¤È¤µ¤ì¤Æ¤¤¤ë.
  • N-rasÊѰۤÏMGUS¤Ç¤âǧ¤á¤é¤ì¤ë¤¬, ¹ü¿ñ¼ð¤Ë¿Ê¹Ô¤¹¤ë¤ÈÌó20%¤ËÁý²Ã¤¹¤ë.
  • c-Myc¤Î¶¯È¯¸½¤â¹ü¿ñ¼ð¤Ë¿ÊŸ¤¹¤ë¤ÈÌó15%¤Î¾ÉÎã¤Ë½Ð¸½¤¹¤ë.
  • ¹ü¿ñ¼ð¤Ë¤ª¤±¤ëc-Myc¶¯È¯¸½¤Î¥á¥«¥Ë¥º¥à¤Ë¤Ïž¼Ì°ø»ÒBRD4¤Îc-Myc°äÅÁ»Òsuper-enhancer¤Ø¤ÎºîÍѤ¬¤¢¤ë¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.*34
  • CpG¥¢¥¤¥é¥ó¥É¤ÎÄã¥á¥Á¥ë²½¤ÏMGUS¢ªMM¿ÊŸ¤Ë¤ß¤é¤ì¤ë3¤Ä¤á¤Î¸½¾Ý. genomeÉÔ°ÂÄêÀ­¤Î¸¶°ø¤È¤Ê¤ê, ¤µ¤é¤Ê¤ëÀ÷¿§Âΰ۾ï¤ò¤­¤¿¤¹¤³¤È¤Ë¤Ê¤ë.
     

¹ü¿ñ¼ð¤Î lineal clonal evolution model.(±¦, Morgan GJ, et al¤Î¿Þ)

14qžºÂ/ À÷¿§ÂιâÆóÇÜÂ⽤ò¥É¥é¥¤¥Ð¡¼ÊѰۤȤ·¤Æ, ·Á¼ÁºÙ˦¤¬¹ü¿ñ¼ð´´ºÙ˦¤ØÅ¾²½¤¹¤ë.
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MUGUS -> ¤¯¤¹¤Ö¤ê·¿¹ü¿ñ¼ð ¢Í ¾É¸õÀ­¹ü¿ñ¼ð ¢Í plasma cell leukaemia¤ò´Þ¤à¿ñ³°¼ðáç¤Ø¤ÎľÀþŪ¿ÊŸ¤òµ¯¤³¤¹.
¿ÊŸ¤Ëȼ¤¤ÉÂÂÖ¤ÏÊ£»¨²½¤¹¤ë. ¼£ÎÅÄñ¹³À­¤¬Áý¤¹¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.

 

¶áǯ¤ÎNGS¤ä¹â´¶ÅÙ¥¢¥ì¥¤¤ÎʬÀϤˤè¤ë¹ü¿ñ¼ð¥¯¥í¡¼¥ó¿Ê²½¤ÎÃθ«

FISH¤ÇIgH-FGFR3¤Ê¤¤¤·TP53 del(17p)¤¬¸¡½Ð¤µ¤ì¤ë¤« PET-CT¤Ç2.5­Ñ°Ê¾å¤ÎÉÂÊѤ¬¤¢¤ì¤Ð¹â¥ê¥¹¥¯¾ÉÎã¤È¤·¤Æ¼£ÎÅÊý¿Ë¤ò¤¿¤Æ¤ë.*35

¤¹¤Ç¤ËMGUS¤ÎÃʳ¬¤Ç¿Íͤʥµ¥Ö¥¯¥í¡¼¥ó¤¬Â¸ºß¤·Ê£»¨¤Ê³¬Áع½Â¤¤ò¤È¤ë¤³¤È¤¬ÌÀ¤é¤«¤Ë¤Ê¤Ã¤¿.

ÉÂÂÖ¿ÊŸ¤ÎËÜÂÖ¤ÏÊѰۤÎÃßÀѤè¤ê¤â, ¥¯¥í¡¼¥ó¹½Â¤¤ÎÊѲ½¤¹¤Ê¤ï¤Á¥¯¥í¡¼¥ó¿Ê²½¤¬¼çÂΤȹͤ¨¤é¤ì¤ë¤è¤¦¤Ë¤Ê¤Ã¤¿.*36

MUGUS -> ¤¯¤¹¤Ö¤ê·¿¹ü¿ñ¼ð ¢Í ¾É¸õÀ­¹ü¿ñ¼ð ¢Í plasma cell leukaemia¤ò´Þ¤à¿ñ³°¼ðáç¤Ø¤Î¿ÊŸ¤È¥¯¥í¡¼¥ó¿Ê²½¤Ï¤É¤Î¤è¤¦¤Ë¤«¤«¤ï¤Ã¤Æ¤¤¤ë¤Î¤«¡©

  • post germinal center B-cell¤Ë14qžºÂ¤¢¤ë¤¤¤ÏÀ÷¿§ÂιâÆóÇÜÂ⽤¬¥É¥é¥¤¥Ð¡¼ÊѰۤȤʤê¹ü¿ñ¼ð´´ºÙ˦¤¬·ÁÀ®¤µ¤ì¤ë¤³¤È¤¬Â¿È¯¹ü¿ñ¼ðȯ¾É¤ÎºÇ½é¤Î¥¹¥Æ¥Ã¥×.
  • ¹ü¿ñ¼ð´´ºÙ˦¤ÏMGUS¤ÎÃʳ¬¤ÇÉÔ¶ÑÅùʬÎö¤Ë¤è¤ê3¡Á6¸Ä¤Î¥¯¥í¡¼¥ó¤ò»ºÀ¸¤¹¤ë. *37
  • ¤³¤ì¤é¤Î½é´üÃʳ¬ MGUS¥¯¥í¡¼¥ó(ancestral clones)¤Î¤¦¤Á¤¤¤º¤ì¤«¤Ë,Ras point mutation¤äc-Myc¶¯È¯¸½¤Ë¤è¤ëÁý¿£Í¥°ÌÀ­(growth advantage)³ÍÆÀ¤¬¤ª¤³¤ë¤Ètumor burden¤¬ÁýÂ礷, MGUS¤«¤é¿ȯ¹ü¿ñ¼ð¤Ø¿ÊŸ¤¹¤ë.
  • ¥¢¥ß¥Î»ÀÊѰۤòȼ¤¦1±ö´ðÊѰÛ(non-synonymous single nucleotide variant)¤ÎÊ¿¶Ñ¿ô¤Ï MGUS 13¸Ä, SMM 28¸Ä(20-69), ¾É¸õÀ­¹ü¿ñ¼ð¤Ç¤Ï31¸Ä(15-46), PCL¤Ë¤Ï59¸Ä(50-68)¤Ç¤¢¤ê¿ÊŸ¤Ëȼ¤¤°äÅÁ»Ò°Û¾ï¤¬ÃßÀѤ·¤Æ¤¤¤¿. [Walker et al¤Ë¤è¤ëNGS²òÀÏ*38]--ÆÃ¤ËMGUS¤«¤éSMM¤Ø¤Î¿ÊŸ¤Ë¤µ¤¤¤·¤ÆRas family¤ÎÅÀÆÍÁ³ÊѰ۽и½¤¬´Ñ»¡¤µ¤ì¤ë.
  • ¥«¡¼¥Í¥ëÌ©ÅÙ¶ÊÀþ¤Ë¤è¤ë¥¯¥í¡¼¥ó¹½Â¤²Ä»ë²½¤Ë¤è¤ê¤¹¤Ç¤ËMGUS¤ÎÃʳ¬¤è¤êÌÀ¤«¤Ê¥¯¥í¡¼¥ó¿ÍÍÀ­¤¬Â¸ºß¤·, ¤É¤ÎÃʳ¬¤Ë¤ª¤¤¤Æ¤â3-6¸Ä¤Î¥¯¥í¡¼¥ó¤¬¸¡½Ð¤µ¤ì¤¿.
  • MGUS¤Ç¸ºß¤¹¤ëÊ£¿ô¤Î¥¯¥í¡¼¥ó¤Î¤¦¤Á, Áý¿£¤ÎÀ¹¤ó¤Ê¥¯¥í¡¼¥ó¤¬³ÈÂ礷¿ȯÀ­¹ü¿ñ¼ð¤Ë¿Ê¹Ô¤¹¤ë¤¬,
    ¾Êý¾ÃÌǤ¹¤ë¥¯¥í¡¼¥ó¤â¤¢¤ê(clonal tide), total¤Î¥¯¥í¡¼¥ó¿ô¤Ë¤ÏÂ礭¤ÊÊѲ½¤Ï¤ß¤é¤ì¤Ê¤¤.
     

¿ȯÀ­¹ü¿ñ¼ð¤Î¥¯¥í¡¼¥ó¿Ê²½¤Ë¤Ï2¼ïÎà¤Î¥Ñ¥¿¡¼¥ó¤¬Â¸ºß¤¹¤ë. ¥¯¥í¡¼¥ó¿Ê²½¤Î¥Ñ¥¿¡¼¥ó¤ÏÆÈΩ¤·¤¿Í½¸å°ø»Ò¤Ç¤¢¤ê¼£ÎÅË¡ÁªÂò¤Î¥Ñ¥é¥á¡¼¥¿¤Ë¤Ê¤ë

  • MGUS¤Ç¸ºß¤¹¤ëÊ£¿ô¤Î¥¯¥í¡¼¥ó¤Î¤¦¤Á, Áý¿£¤ÎÀ¹¤ó¤Ê¥¯¥í¡¼¥ó¤¬³ÈÂ礷¿ȯÀ­¹ü¿ñ¼ð¤Ë¿Ê¹Ô¤¹¤ë¤¬,
    ¾Êý¾ÃÌǤ¹¤ë¥¯¥í¡¼¥ó¤â¤¢¤ê(clonal tide), total¤Î¥¯¥í¡¼¥ó¿ô¤Ë¤ÏÂ礭¤ÊÊѲ½¤Ï¤ß¤é¤ì¤Ê¤¤.
  • SMM¤«¤é¾É¸õÀ­Â¿È¯À­¹ü¿ñ¼ð¤Ø¤Î¿ÊŸ¤Ï°äÅÁ»ÒÊѲ½¤ÎÁý²Ã¤Ç¤Ï¤Ê¤¯, ¥¯¥í¡¼¥ó¹½Â¤¤ÎÊѲ½¤Ë¤è¤ë¤â¤Î¤È¹Í¤¨¤é¤ì¤Æ¤¤¤ë.
     
  • ½éȯ»þ¹ü¿ñCD138ÍÛÀ­ºÙ˦¤ÎÌÖÍåŪÅÀÆÍÁ³ÊѰ۲òÀϤ«¤é, 80%¤ÏÊѰÛÃßÀѤ¬Ä¾ÀþŪ¤Ç¤Ê¤¯, ¥¯¥í¡¼¥ó¤¬»Þʬ¤«¤ì¤·¤Ê¤¬¤é¿ÊŸ¤¹¤ë»Þʬ¤«¤ì¿Ê²½(¥À¡¼¥¦¥£¥ó¤¬¼ï¤Îµ¯¸»¤ÇÄ󾧤·¤¿)¤ò¤È¤Ã¤¿.
     
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    • ¤³¤Î¥¿¥¤¥×¤Ï¹ü¿ñ´Ö¼ÁºÙ˦¤äÌȱֺÙ˦¤È¤ÎÁê¸ßºîÍѤ¬¶¯¤¯, ¤½¤ì¤é¤ËºîÍѤ¹¤ë thalidomide¤älenalidomide¤Ê¤Éimmunomodulatory drugs(IMiDs)¤¬ÁÕ¸ù¤¹¤ëÎ㤬¿¤¤.
       
  • ÃæÎ©¿Ê²½·¿Â¿È¯À­¹ü¿ñ¼ð: ¥É¥é¥¤¥Ð¡¼ÊѰۤò¸¶Æ°ÎϤȤ·¤Æ¥¯¥í¡¼¥ó¤¬Ä¾ÀþŪ¤ËÁý²Ã¤·¤Æ¤¤¤¯. t(4;14)¤ät(14;16)¤Ê¤É¤Î¹â¥ê¥¹¥¯°Û¾ï¤ò´Þ¤à14qžºÂ¤Î¾ì¹ç¤Ï¤³¤Î¥¿¥¤¥×¤Î¿Ê²½¤ò¤È¤ë¤³¤È¤¬Â¿¤¤.
     
    • ͽ¸åÉÔÎɤÎÀ÷¿§ÂΞºÂ¤ò¤â¤Á, ¿ÊŸ¤âÁ᤯, IMiDs¤Ë²Ã¤¨¤Æ, ¥×¥í¥Æ¥¢¥½¡¼¥àÁ˳²Ìô¤ä¤·ì´´ºÙ˦°à½Ì¤Ê¤É¶¯Îϼ£ÎŤòɬÍפȤ¹¤ë.
       
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¼£ÎÅÄñ¹³À­¤Î¸¶°ø¤È¤Ê¤ëÆÃÄê¤Î°äÅÁ»ÒÊѰۤäÀ÷¿§Âι½Â¤°Û¾ï¡¡--17p·ç¼º¤ª¤è¤Ó1qÁýÉý¤Î¥¯¥í¡¼¥ó¿ÊŸ¤È¤Î´Ø·¸¤ÈÌôºÞÂÑÀ­¤Î¥á¥«¥Ë¥º¥à

17p deletion;

  • ½éȯ¿ȯÀ­¹ü¿ñ¼ð(NDMM)¤Î10%¤Ë¸¡½Ð¤µ¤ì¤ë. ÉÂÀª¿Ê¹Ô¤È¤È¤â¤ËÁý²Ã¤·ºÆÈ¯¡¦Æñ¼£À­Â¿È¯À­¹ü¿ñ¼ð(RRMM), ¤È¤¯¤Ë¿ñ³°ÉÂÊѤòȼ¤¦Îã¤äPCL¤Ç¤Ï50-70%d¤Çǧ¤á¤é¤ì¤ë. *39
     
    • ·ç¼ºÈϰϤϾÉÎã¤Ë¤è¤ê°Û¤Ê¤ê, ûÏÓÁ´ÂΤη缺¤«¤é1Mb°Ê²¼¤ÎÉôʬ·ç¼º¤Þ¤Ç¤µ¤Þ¤¶¤Þ.
       
    • ¶¦Ä̤·¤ÆÌó20¤Î°äÅÁ»Ò¤Îȯ¸½¤¬Äã²¼¤¹¤ë¤ÈÊó¹ð¤µ¤ì¤Æ¤¤¤ë. ¤½¤ÎÃæ¤Ç¤¬¤óÍÞÀ©°äÅÁ»ÒTP53¤¬ºÇ¤â½ÅÍפǤ¢¤ë.
       
    • 17p·ç¼º¤Ë¤è¤êp53ȯ¸½Î̤¬1/2¤ËÄã²¼¤¹¤ë¤Èhaploinsufficiency¤Ë¤è¤êµ¡Ç½¤¬1/2°Ê²¼¤Ë¸º¼å, ¹³¤¬¤óºÞ¤äÊü¼ÍÀþ¤Ë¤è¤ëDNA»½ý¤Ø¤Î±þÅúÉÔÁ´¤È¤Ê¤ê¥¢¥Ý¥È¡¼¥·¥¹Í¶Æ³¤¬ÍÞÀ©¤µ¤ì¼£ÎÅÄñ¹³À­¤È¤Ê¤ë.
       
    • DNA½¤ÉüǽÄã²¼¤Ë¤è¤ëÆó¼¡À­°äÅÁ»ÒÊѰÛͶȯ¤¬¤ª¤³¤ë. ¤È¤¯¤ËÂЦallele¤ÎTP53(@17p13.1)ÅÀÆÍÁ³ÊѰۤ¬ÌäÂê¤È¤Ê¤ë.
       
    • ¿ȯÀ­¹ü¿ñ¼ð¤Ç¤Ïde novo TP53ÊѰۤÏÈæ³ÓŪ¾¯¤Ê¤¯, 17p·ç¼º¤Ë¹çÊ»¤¹¤ë¤³¤È¤¬Â¿¤¤.*40
       
    • TP53ÊѰۤÏ17p·ç¼º¤Î40-50%¤Ë¹çÊ»¤¹¤ë¤È¤µ¤ì¤ë. total¤ÎÉÑÅÙ¤ÏNDMM¤Ç5¡Ý8%, RRMM¤ÇÌó25%. *41
  • ½éȯ¿ȯÀ­¹ü¿ñ¼ð 1273Îã¤Î17p·ç¼ºclonality¤òcancer clonal fraction(CCF)¤È¤·¤Æ¼¨¤·¤¿Êó¹ð*42¤Ç¤Ï, 17p·ç¼º¤Ï108Îã(3.4%)¤Ëǧ¤á¤é¤ì¤¿¤¬CCF¤Ï¤Û¤ÜÁ´Îã80%̤Ëþ¤Ç¤¢¤ê17p·ç¼º¤Ïsubclonal¤Ë¤ª¤³¤Ã¤Æ¤¤¤ë¤È³Îǧ¤µ¤ì¤Æ¤¤¤ë.
  • CCF¤Ïͽ¸å¤ÈµÕÁê´Ø¤·¤Æ¤¤¤ë. : CCF>0.55¤Î¾ÉÎã¤Ç¤ÏCCF¡å0.55Îã¤ËÈæ¤Ù¤ÆÍ­°Õ¤Ëͽ¸åÉÔÎɤǤ¢¤Ã¤¿.(PFS14.3¥õ·î, OS36.0¥õ·î vs PFS23.9¥õ·î OS 84.1¥õ·î)
  • TP53ÊѰۤÏCCF>0.55¾ÉÎã¤ËÌÀ¤é¤«¤Ë¿¤¯Ç§¤á¤é¤ì¤¿. (CCF¡å0.55¤Î¾ÉÎã¤Ç¤Ï2.3%(1/44Îã) vs CCF>0.55¤ÎÎã¤Ç¤Ï42.2%(27/64Îã))
  • CCF>0.55Îã¤Ç¤âTP53ÌîÀ¸·¿¾ÉÎã¤Ç¤Ï, PFS/OS¤ÏCCF¡å0.55¤ÎÎã¤È¤«¤ï¤é¤Ê¤«¤Ã¤¿¤¬, TP53ÊѰÛÎã¤Ç¤Ï¤­¤ï¤á¤ÆÍ½¸åÉÔÎɤǤ¢¤Ã¤¿.
  • TP53ÊѰۤòÄêÎÌŪ¤Ë²òÀϤ¹¤ëÂå¤ï¤ê¤Ë, ·ì¾®ÈÄ¿ôÄã²¼¤ÈLDH¤¬Î×¾²Åª¥Ñ¥é¥á¡¼¥¿¤È¤·¤Æ¹âÁê´Ø¤ò¼¨¤·ÍøÍѲÄǽ¤Ç¤¢¤ë*43.
  • p53µ¡Ç½·ç»ºÙ˦¤Ç¤Ï¥°¥ë¥³¡¼¥¹¼è¤ê¹þ¤ß¤¬¹â¿Ê¤¹¤ë¤¿¤á, PET¥·¥°¥Ê¥ë¶¯ÅÙ¤¬Áý²Ã¤·, ½Ä³Ö¤ËÂФ¹¤ë¼ðáç¤Î¥·¥°¥Ê¥ë¶¯ÅÙÈæ¤¬2.5°Ê¾å¤Î¾ì¹ç¤Ïp53¤ËÊѰۤ¬¤¢¤ë²ÄǽÀ­¤¬¹â¤¤.
  • p53ÊѰۤò¤â¤Ä¾ÉÎã¤Ç¤Ï, ¿ñ³°ÉÂÊѤ¬72.7%¤Ëǧ¤á¤é¤ì¤¿.

½é¿Ç»þ¤Ë17p·ç¼º¤ò¤ß¤È¤á¤¿¾ì¹ç, TP53ÊѰ۹çÊ»¤òËɤ°¤¿¤á, ¤·ì´´ºÙ˦°Ü¿¢¤ò¤Õ¤¯¤á¤¿¶¯ÎÏ¤ÊÆ³ÆþÎÅË¡¤ò¤ª¤³¤Ê¤¤17p·ç¼º¾ÉÎã¤Ø¤ÎÍ­¸úÀ­¤¬¼¨¤µ¤ì¤Æ¤¤¤ëpomalidomide¤ò´Þ¤à¼£ÎŤǥե©¥í¡¼¤¹¤ë¤³¤È¤¬Ë¾¤Þ¤·¤¤.

 
 

1qÁýÉý Èæ³ÓŪºÇ¶á¤Ë¤Ê¤êͽ¸å¤Ø¤Î±Æ¶Á¤¬ÌÀ³Î¤Ë¤Ê¤Ã¤¿¹½Â¤°Û¾ï. *44*45*46

  • ¹â¥ê¥¹¥¯°Û¾ï¤ÎÃæ¤Ç¤âÉÑÅÙ¤¬ºÇ¤â¹â¤¯, NDMM¤ÎÌó40%, RRMM¤Ç¤Ï50-70%¤ËÁý²Ã¤¹¤ë.*47
     
  • copy¿ôÁý²Ã¤Ï1q21¤Ë¸Â¶É¤·¤Æ¤¤¤ë. 3copy°Ê¾å¤ÎÁýÉý¤ò1q gain¤È¤·, 4copy°Ê¾å¤Î¾ì¹ç¤ò1q amplification¤ÈÄêµÁ¤¹¤ë.*48
     
  • copy¿ô¤Èͽ¸å¤ÏµÕÁê´Ø¤¹¤ë¤¿¤á, 1q21¤Ë°ÌÃÖ¤¹¤ë°äÅÁ»Òȯ¸½Ð¶¿Ê¤¬¸¶°ø¤È¹Í¤¨¤é¤ì¤ë¤¬¾ÜºÙ¤Ï¤Þ¤ÀÉÔÌÀ--BCL9, MCL1, IL6RA, CKS1B(CDC28 protein kinase regulatory subunit 1B), ANP32E(acidic nuclear phosphoprotein 32 family member E), ARNT(aryl hydrocarbon receptor nuclear translocator) ¤Ê¤É.*48
     
  • 1qÁýÉý¤Ï¹â¥ê¥¹¥¯14qžºÂ¤Ë¤è¤ëºÙ˦Áý¿£Ð¶¿Ê¤Ëȼ¤¦Ê£À½¥¨¥é¡¼¤ä¥²¥Î¥àÉÔ°ÂÄêÀ­¤òÇØ·Ê¤È¤·¤Æ½Ð¸½¤¹¤ë²ÄǽÀ­¤¬¤¢¤ë.
     
    • 553Îã¤ÎMM¾ÉÎã¤Ç, FISH¤Ç1qÁýÉý¤ò¤·¤é¤Ù¤¿201Îã¤Î¥µ¥Ö²òÀÏ*49¡§1qÁýÉý¤¢¤ê46.8%(94/201), 1qÁýÉýÍÛÀ­¾ÉÎã¤ÎPFSÃæ±ûÃÍ ¤Ï±¢À­Îã¤Ë¤¯¤é¤ÙÍ­°Õ¤Ëû¤«¤Ã¤¿. (+ 41.9¥õ·î vs - 61.5¥õ·î)
       
  • ¼£ÎŤȤ·¤Æ¤Ï, VRdÎÅË¡¤ädaratummab-based regimens¤Ç¤ÏºÆÈ¯¤Î¿¤¤¤³¤È¤¬Êó¹ð¤µ¤ì, ¿·µ¬CD38¹³ÂÎ istuximab¤Èpomalidomide-dexamethasone¤ÎÁȤ߹ç¤ï¤»¤¬´üÂÔ¤µ¤ì¤Æ¤¤¤ë.
     
     

¿ȯÀ­¹ü¿ñ¼ð¤Îintratumoral heterogenity

  • MM¤Ç¤ÏÉÂÊÑÉô°Ì¤Ë¤è¤ë¥µ¥¤¥º, ÁýÂç®ÅÙ, ¼£ÎÅÈ¿±þÀ­¤Î°ã¤¤¤¬¤·¤é¤ì¤Æ¤¤¤ë. ---°äÅÁ»Ò°Û¾ï¤È¤³¤Î»þ¶õŪ¿ÍÍÀ­¤Î´ØÏ¢¤òÄ´ººPET-CT¤Ç¸¡½Ð¤µ¤ì¤¿ÉÂÊÑ(FL; ¾ÉÎ㤢¤¿¤ê1-4¥«½ê)¤òIJ¹üÉÂÊѤÈÈæ³Ó. [½éȯMM 42, ºÆÈ¯11Îã]*50
  • Éô°Ì¤Ë¤è¤ë, À÷¿§Âι½Â¤°Û¾ï¤Î°ã¤¤¤Ï40%¤Î¾ÉÎã¤Ëǧ¤á¤é¤ì¤¿.
  • driverÊѰۤˤÏÉô°Ì¤Ë¤è¤ë¿ÍÍÀ­¤¬¤ß¤é¤ì¤Ê¤¤; 14qžºÂ¤Ï22ÎãÁ´Îã, À÷¿§ÂιâÆóÇÜÂ⽤Ï31/33Îã¤Ç¤¹¤Ù¤Æ¤ÎÉô°Ì¤Ë¸¡½Ð¤µ¤ì¤¿.
  • 17p·ç¼º¤Ï2/6(33%)Îã¤Ë, MycžºÂ¤Ï4/16(25%)¤ËÉô°ÌÆÃ°ÛÀ­¤¬¤ß¤é¤ì¤¿.
  • °äÅÁ»ÒÊѰۤˤĤ¤¤Æ¤Ï, 75%¤Î¾ÉÎã¤ËÉô°Ì¤Ë¤è¤ë°ã¤¤¤¬Ç§¤á¤é¤ì¤¿.
  • MAP kinase ·ÐÏ©¤Ë´ØÍ¿¤¹¤ëʬ»Ò¤ÇÉô°Ì¤Ë¤è¤ë°ã¤¤¤¬Â礭¤¤; N-RasÊѰÛ(8/29), K-Ras(9/18), B-Raf(3/8)
  • p53ÊÑ°Û¤Ï 3/9Îã¤ËÉô°ÌÆÃ°ÛÀ­¤¬Ç§¤á¤é¤ì¤¿.
  • FL¤Ïsubclone¤¬¶É½ê¤ËÄêÃ夷, ÄêÃå¾ì½ê¤È¤ÎÁê¸ßºîÍѤˤè¤ê¿ÊŸ¤·¤¿¤â¤Î¤È¹Í¤¨¤é¤ì¤ë.
  • FL¤Ë¤Î¤ß¹â¥ê¥¹¥¯°Û¾ï¤¬¸«¤é¤ì¤¿¾ì¹ç, IJ¹ü, FL¤È¤â¤Ë¹â¥ê¥¹¥¯°Û¾ï¤òÄ褷¤¿¾ÉÎã¤ÈƱÍÍ OS¤¬Ã»¤¤.
  • FL¤Î¥µ¥¤¥º¤ÈÉô°Ì¤Ë¤è¤ëÊѰÛ¿ÍÍÀ­¤ÏÁê´Ø¤·¤Æ¤¤¤ë. ¹ü¿ñ¸¡ÂΤΤߤǥꥹ¥¯¤òɾ²Á¤¹¤ë¤È°­À­ÅÙ¤òÄ㤯¸«ÀѤâ¤ë´í¸±À­¤¬¤¢¤ë.
  • PET-CT¤Ç2.5cm°Ê¾å¤ÎÉÂÊѤϹâ¥ê¥¹¥¯¤È¹Í¤¨¤é¤ì¤ë.

¹ü¿ñ¼ð´´ºÙ˦¤¬»Ä¸¤¹¤ë¤È¥¯¥í¡¼¥ó¿Ê²½¤¬ºÆ¸½¤µ¤ì¤ë¤¿¤á*51,¹â¥ê¥¹¥¯¾ÉÎã¤Ë¤Ä¤¤¤Æ¤Ï¼£ÎŤηѳ, ¤È¤¯¤Ë¥×¥í¥Æ¥¢¥½¡¼¥àÁ˳²Ìô¤ò´Þ¤à¥ì¥¸¥á¥ó¤¬É¬¿Ü¤Ç¤¢¤ë. 1qÁýÉý¤â½é¿Ç»þ¤Ë¸¡ºº¤·½é¿Ç»þ±¢À­¤Ç¤âºÆÈ¯»þ¤Ë¤ÏºÆ¸¡ºº¤¹¤ë¤³¤È¤¬Ë¾¤Þ¤·¤¤.


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*3  Sato K, et al. PAX5-positive plasma cell myeloma with t(9;14;11)(p13;q32;q13), a novel complex variant translocation of t(11;14)(q13;q32) and t(9;14)(p13;q32).Int J Hematol. 2015 Jun;101(6):608-11.
*4  Nakagawa Y et al., Clinical implications of abnormalities of chromosomaes 1 and 13 in multiple myeloma. Acta Haematol 109; 129-136: 2003
*5  ÁÒ¶¶¿®¸ç¤Û¤«¡§Â¿È¯À­¹ü¿ñ¼ð¤Ë¤ª¤±¤ëÀ÷¿§Âΰ۾ï¤ÎÉÑÅÙ¤Èͽ¸å¤Ø¤Î±Æ¶Á¡¡Î×¾²·ì±Õ48; 1455-1461: 2007
*6  Chesi Marta et al., Molecular pathogenesis of multiple myeloma: basic and clinical updates Int J Hematol 2013; 97: 313-323
*7  Fonseca R, et al., Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003 Jun 1;101(11):4569-75. Epub 2003 Feb 6.
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*22  ÍûÀ¯¼ù¤Û¤«¡¡¹ü¿ñ¼ð¤Ë¤ª¤±¤ëž¼Ì°ø»Ò¤Î°Û¾ïȯ¸½¡¡°å³Ø¤Î¤¢¤æ¤ß 242(13); 994-1001: 2012
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*25  Kuo AJ, et al., NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming.Mol Cell. 2011 Nov 18;44(4):609-20.
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*33  ÈÓÅÄ¿¿²ð À÷¿§ÂΡ¦¥²¥Î¥à¸¡ºº¤Î¹ü¿ñ¼ð´µ¼Ô¤Ø¤ÎÎ×¾²Å¸³« ÆüËÜÀ÷¿§ÂΰäÅÁ»Ò¸¡ºº 2017; 35(1): 23-28
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*39  Jovanovi KK, et al. Deregulation and Targeting of TP53 Pathway in Multiple Myeloma Front Oncol 2019 Jan 9;8:665.doi: 10.3389/fonc.2018.00665. eCollection 2018. PMID: 30687640
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*46  Varma A, et al.Outcome of Multiple Myeloma with Chromosome 1q Gain and 1p Deletion after Autologous Hematopoietic Stem Cell Transplantation: Propensity Score Matched Analysis. Biol Blood Marrow Transplant 2020 Apr;26(4):665-671.PMID: 31881283
*47  Hanamura I, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood. 2006 Sep 1;108(5):1724-32.PMID: 16705089
*48  Pawlyn C, et al. Evolutionary biology of high-risk multiple myeloma. Nat Rev Cancer 2017 Aug 24;17(9):543-556.PMID: 28835722
*49  Schmidt T, et al. Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone Blood Cancer J 2019 Nov 25;9(12):94. PMID: 31767829
*50  Rasche L, et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing.Nat Commun. 2017 Aug 16;8(1):268.PMID: 28814763
*51  Jones JR, et al. Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients. Haematologica. 2019 Jul;104(7):1440-1450.PMID: 30733268

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