1. Epidemiology of Chronic Myeloid Leukemia Tom Radivoyevitch, PhD Assistant Professor Epidemiology and Biostatistics Case Western Reserve University

2. Two CML-ogens: Radiation and Age Not exponential => use additive risk model Sv = gamma ray dose (Gy) + 10 neutron dose (Gy)

3. Radiation-induced CML is Multi-scale Figure by R.K. Sachs. For a 500 keV incoming photon J = 6.2e18eV Gy = J/kg = 6.2e6eV/pL

4. Stochastic versus Deterministic Figure by R.K. Sachs.

5. Why Study Radiation as the Input? Best carcinogen exposure assessment: A- bomb survivors remember exactly where they were, so doses can be reconstructed Compared to chemical carcinogen, cannot simply not use it: background, diagnostic, and therapeutic exposures are here to stay Physics is understood, so results across x- & γ -rays, neutrons & protons, and α- and β particles at different energies can be unified Other CML-ogen, aging, also cannot be avoided+exposure is known

6. Why Study CML as the Output? CML is homogeneous: all have BCR-ABL CML is prevalent: introns large => per-cell target size for creating bcr-abl is large leukemias have rapid onset kinetics: white blood cells go in and out of tissues naturally so they don’t need to learn to metastasize Chr9 = 136.3 Mb ~140 kb 139.6 Kb DNA Repair 10 (2011) 1131– 1137 ~5 kb = introns between e12-e15 Chr 22 49.2 Mb From 1KG browser

7. PML-RARA intron sizes ~20kb Seer APL/CML 1234/10103 = 12%=1/8 40/700=1/18 40%,55% Mediterr J Hematol Infect Dis. 2011;3(1) ~2kb

8. Dose Response N is the number of CML target cells in an individual P(ba|T) is the probability of BCR- ABL given a translocation w(t)=probability density that CML arrives at t given bcr-abl at t=0 Linear R = 0.0075/Gy. LQE posterior R = 0.0022/Gy

9. CML Target Cell Numbers A comparison of age responses for CML and total translocations suggests a CML target cell number of 4x10 8 10 12 nucleated marrow cells per adult and one LTC-IC per 10 5 marrow cells suggests 10 7 CML target cells P(ba|T) = 2T abl T bcr /  2 may not hold

10. Kozubek et al. (1999) Chromosoma 108: 426-435 BCR-to-ABL 2D distances

11. 23 Hi-C Data http://hic.umassmed.edu/heatmap/heatmap.php 133 chr9 chr22 K562 = bcr-abl + CML cells Lieberman-Aiden, et al. Science 9 October 2009: 289-293. 23 133 GM06690 = EBV-transformed lymphoblasts Off by 2 Mb?

12. Theory of Dual Radiation Action P(ba|D) = probability of a BCR-ABL translocation per G 0 /G 1 cell given a dose D t D (r)dr = expected energy at r given an ionization event at the origin = intra-track component + inter-track component S ba (r) = the BCR-to-ABL distance probability density g(r) = probability that two DSBs misrejoin if they are created r units apart Y = 0.004 DSBs per Mb per Gy;  = mass density T BCR = 5.8 kbp; T ABL = 140 kbp

13. Total Translocations → g(r) estimate G=25 DSB/Gy 6.25 kev/  m 3 = 1 Gy R = 3.7  m  r 0 = 0.24  m, p 0 = 0.12  d  in [.01,.025],  dx in [.04,.05],  d in [.05,.06]

14. Risk and Target Cell Numbers  Higher risk estimate is more biologically plausible Linear-to-quadratic transition dose changed from [0.011-0.022]/0.055= [0.2-0.4] Gy to 3.64/.45= 8.09 Gy Linear R = 0.0075/Gy for D < 4Sv is higher here at 0.0094/Gy due to cell killing term

15. Bcr-Abl to CML Waiting Times M/F=1.42 tf-tm=6.3y M/F=1.6 tf-tm=10 yrs

16. Age at Exposure Dependence

17. Nagasaki HSC Reserve Loss? 6 Nagasaki CML vs 53 in Hiroshima Hiroshima PY=1558995 Nagasaki PY= 690084 (i.e. 2.26 lower), 53/2.26 = ~23 cases expected in Nagasaki HSC reserve permanently depleted to 25%? Human T-cell leukemia virus (HTLV): 22 adult T-cell leukemias (ATLs) in Nagasaki compared to 1 in Hiroshima (2.26 more PY => expect ~50)

18. Dead-Band Control of HSC levels Transplant doses of 10, 100, and 1000 CRU => CRU levels 1-20% or 15-60% normal Blood (1996) 88: 2852-2858 Broad variation in human HSC levels Stem Cells (1995) 13: 512-516 Low levels of HSCs in BMT patients Blood (1998) 91: 1959-1965

19. HSC Reserve Loss Trend? Ave last 7 ratios 0.70 0.49 1995 data yielded k= 0.041 [Radiat Environ Biophys (1999) 38:201–206]. 0.031 in 2006 is consistent with tlcns leading CML by 10 yrs 0.80 0.54

20. All Cancer Incidence Conclusion: Cancer therapy is not the cause of the HSC reserve depletion Other Guesses? Does obesity increase bone marrow fat and thus squeeze out HSC? 1. Mississippi (34.4%) 51. Colorado (19.8%) 0.1*x+1(1-x)=0.5 =>.5=.9x => x=.555 Prevalence of cause must be greater than 55% Cancer Epidemiol Biomarkers Prev 2009;18:1501-1506 => obesity causes CML Easier travel=> greater loads on immune system?

21. Or is it CMML Misclassification? CML = ICDO-2 9863 does not include CMML. Maybe all were called CML <1985, 50% in 1985-1995, and 0 after CML=ICD9 205.1 includes 20% CMML

22. CMML rises at older ages ICDO-2 9945 = CMML Counts of CMML per year. None before 1985 1984 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 1 40 41 43 50 53 70 61 68 66 65 79 93 65 85 78 82 87 2003 2004 2005 2006 2007 2008 2009 93 127 84 91 104 80 123

23. AML More APL or better diagnostics?

24. Retinoic Acid and Imatinib Cures found for cancers that are molecularly homogeneous: simpler cancers are being solved first

25. AML and CLL More typically progress is slower

26. Acknowledgements Department of Epidemiology & Biostatistics Rainer Sachs (UC Berkeley) Yogen Saunthararajah (Cleveland Clinic) Thank you for listening!

27. SEER Underreporting Possibility Most conservative claims-based algorithm vs. SEER. B. M. Craig et al. Cancer Epidemiol Biomarkers Prev; 21(3) March 2012

28. Radiation Doses Rising

29. AML Assuming all CML-ogens are also AML-ogens, this implies CML decreases are NOT due to decreases in exposures to bcr-abl forming agents. No AML trend is consistent with target cells being lineage committed and thus more tightly regulated than HSCs.

30. Others

31. All Cancer Incidence

33. Nagasaki HSC Reserve Loss? Hiroshima Nagasaki 6 Nagasaki CML vs 53 in Hiroshima Hiroshima PY=1558995 Nagasaki PY= 690084 (i.e. 2.26 lower), 53/2.26 = ~23 cases expected in Nagasaki HSC reserve permanently depleted to 25%? Human T-cell leukemia virus (HTLV): 22 adult T- cell leukemias (ATLs) in Nagasaki compared to 1 in Hiroshima (2.26 more PY => expect ~40)